Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Na]>CN(C=O)C>[N:17]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCc1ccc2ncccc2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: c1cnc2ccc(Cn3ccnc3)cc2c1
Temperature: 70 °C
Yield: 27 %

Procedure:
The title product from Step A above was dissolved in anhydrous DMF (10 mL) and sodium imidazole (0.367 g, 4.08 mmoles) was added. The mixture was heated at 70° C. under argon for 2 h and then evaporated to dryness. The product was chromatographed on silica gel to give the title compound (0. 1559 g, 27%): FABMS: m/z 210.0 (MH+); δH (CDCl3) 5.34 (1H, s, CH2), 6.97 (1H, s, Im-H5), 7.15 (1H, s, Im-H4), 7.44 (1H, dd, Ar—H3), 7.52 (2H, m, Ar—H5 and Ar—H7), 7.64 (1H, s, Im-H2), 8.12 (2H, d, Ar—H4 and Ar—H8) and 8.95 ppm (1H, d, Ar—H2); δC (CDCI3) CH2: 50.6; CH: 119.4, 121.8, 125.9, 128.4, 130.1, 130.5, 136.0, 137.6, 151.0; C: 128.2, 134.6, 147.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].Br[CH2:12][CH3:13].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCCC>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:10])[C:4]=1[F:9])[CH3:13]
Reactant: Oc1ccc(Br)c(F)c1F
Reactant: CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCCC
Product: CCOc1ccc(Br)c(F)c1F
Reaction time: 6 h
Yield: 97 %

Procedure:
To an aqueous (400 ml) solution of 4-bromo-2,3-difluorophenol (T-1) (195.0 g), bromoethane (196.2 g) and tetrabutylammonium bromide (hereinafter, abbreviated as TBAB) (24.2 g), sodium hydroxide (75.9 g) was added, and heating agitation was carried out at 80° C. for 6 hours in a nitrogen atmosphere. After completion of the reaction, extraction was carried out with heptane, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a black oily matter was obtained. The resultant material was purified by distillation, and thus 1-ethoxy-2,3-difluorobromobenzene (T-2) was obtained as a colorless oily matter (230.0 g, yield: 97%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[C:17]([F:32])=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][CH:26]=[CH:27][C:28]=2[F:29])[C:19]([F:22])=[CH:20][CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:20]3[C:19]([F:22])=[C:18]([C:23]4[C:24]([C:30]#[N:31])=[CH:25][CH:26]=[CH:27][C:28]=4[F:29])[C:17]([F:32])=[CH:16][CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4c(F)cccc4C#N)c3F)cnc2c1F
Yield: 10 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as described in Example 6 to give 3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]-6,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid (17 mg, 10%): δH (400 MHz, d6-DMSO) 1.58 (6H, s), 5.56 (1H, s), 7.23 (1H, t, J 7), 7.61 (1H, t, J 8), 7.84-7.87 (3H, m), 7.95-8.01 (2H, m), 8.08 (1H, dd, J 7 and 3); m/z (ES+) 426 [MH+]
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][N:23]([CH3:43])[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:40]3[CH2:41][CH2:42][N:37]([S:34]([C:29]4[C:30]5[C:25](=[C:24]([N:23]([CH3:43])[CH3:22])[CH:33]=[CH:32][CH:31]=5)[CH:26]=[CH:27][CH:28]=4)(=[O:36])=[O:35])[CH2:38][CH2:39]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N3CCNCC3)cccc12
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCN(C(=O)Oc4ccc(Oc5ccc(C(F)(F)F)cn5)cc4)CC3)cccc12
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazine and purified by flash chromatography (ethyl acetate-heptane 1:4), yield 32%. Pale crystals, HPLC-MS: m/z: 601(M+1) at Rt=5.2 min.;m.p. ° C.; IR (KBr): ν 1723 (C═O) cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:31][CH:32]=2)[CH2:13][CH2:12]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C1CCC(NC(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step B of Example 24 (0.020 g, 0.054 mmol) in DMF (2 mL) was added 4-(trifluoromethoxy)benzoic acid (0.0090 g, 0.059 mmol), HOAT (0.0080 g, 0.059 mmol), N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) and HATU (0.022 g, 0.059 mmol). After 24 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with 100 mL of 0.5 M aqueous sodium bicarbonate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by reverse phase HPLC (30%-60% acetonitrile in H20 gradient) afforded the title compound as a white solid. LC/MS 506.3 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].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>CN(C=O)C>[C:17]([O:16][CH2:15][C@H:2]1[NH:1][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH2:5][O:4][CH2:3]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC[C@@H](N)COCc1ccccc1C(=O)O
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: CC(C)(C)OC[C@@H]1COCc2ccccc2C(=O)N1
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of compound 14d (394 mg, 1.4 mmol) and HATU (639 mg, 1.68 mmol) in DMF (20 mL) at rt was added DIPEA (1 mL). The reaction mixture is stirred for 16 h, quenched with H2O and extracted with EA (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CC on silica gel, eluting with PE/EA=4:1 to give compound 14e (171 mg, 46% yield) as a yellow solid.
Reaction SMILES: C[I:2].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36]O)[S:31][C:30]=2[C:38]=1[CH3:39]>CN(C)C=O>[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36][I:2])[S:31][C:30]=2[C:38]=1[CH3:39]
Reactant: CI
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reaction time: 1 h

Procedure:
2 ml of methyl iodide were added to 0.67 g of triphenyl phosphite, and then the temperature of the reaction mixture was raised to reflux temperature, after which the reaction was continued for 1 hour at a bath temperature of 100° C. The temperature of the reaction mixture was reduced to room temperature, and then 0.5 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3,-benzoxathiole-2-yl)propanol (prepared as described in Example 71), 1 ml of methyl iodide and 0.5 ml of dimethylformamide were added to the reaction mixture. The reaction was continued for 3 days at room temperature. At the end of this time, the title compound, having the same properties as the product of (a) above, was obtained by the same treatment and separation procedures as in (a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[Br:18])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:39][C:40](O)([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[C:40]([O:13][C:12](=[O:14])[C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([Br:18])=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)([CH3:42])([CH3:41])[CH3:39]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid (200b) (153 g, 0.37 mol) in DMF (1 L) was added CDI (90 g, 0.56 mol) in several portions. The solution was stirred at 40° C. for 1 hr. t-BuOH (55 g, 0.74 mol) was added to the mixture and then followed by the drop wise addition of DBU (56.3 g, 0.37 mol). The resulting solution was stirred at 40° C. for 2 days. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The mixture was cooled to room temperature and poured into ice water (1 L). The mixture was acidified to pH 5 with conc. HCl and stirred for 1 hr. The formed solid was filtered and washed with water, then dried in vacuo to give the title compound (165 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.57-7.25 (m, 12H), 5.21(s, 4H), 1.58 (s, 9H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:13])=[O:12])=[C:6]([CH3:26])[CH:5]=1>C1COCC1>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:13])=[C:6]([CH3:26])[CH:5]=1
Reactant: COC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N2CCCCC2CCC(=O)O)c(C)cc1Cl
Temperature: 0 °C

Procedure:
Aqueous 6 M NaOH solution (100 ml) was added to a solution of methyl 3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionate (12.82 g, 34.3 mmol) in THF (100 ml). After a reaction time of 1 h, the solvent was removed in a rotary evaporator and the residue was cooled to 0° C. 6 M HCl (100 ml) was added and extraction with ethyl acetate was carried out. The organic phase was dried over Na2SO4 and concentrated. Yield: 12.36 g, 100%
Reaction SMILES: [CH2:1]([CH:3]([CH2:32][CH3:33])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=[C:9]([F:31])[CH:8]=1)=[O:5])[CH3:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:32]([CH:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=[C:9]([F:31])[CH:8]=1)=[O:5])[CH3:33]
Reactant: CCCCC(O)(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of 2-ethyl-N-{3-fluoro-4-[4-(1-hydroxy-1-phenyl-pentyl)-piperidin-1-yl]-phenyl}-butyramide (17 mg, 0.037 mmol) and Et3SiH (0.025 mL) in DCM (0.15 mL) was added TFA (0.25 mL). The mixture was stirred at 25° C. for 0.5 h and purified by PTLC to provide the title compound (9 mg, 55%). MS: 439.4. 1H NMR (CDCl3): 7.40 (dd, J=14.0, 2.5, 1H), 7.32-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.06 (m, 3H), 7.02 (s, 1H), 7.06 (t, J=9.2, 1H), 3.47-3.22 (m, 2H), 2.65-2.55 (m, 1H), 2.52-2.43 (m, 1H), 2.38-2.30 (m, 1H), 2.03 (m, 2H), 1.88-1.15 (m, 12H), 1.10-0.98 (m, 2H), 0.92 (t, J=7.4, 6H), 0.81 (t, J=7.3, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][CH:5]([CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:4][O:3]1.I[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[O:6][CH:5]([CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([O:21][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:4][O:3]1
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Reactant: CC(C)(C)OC(=O)NCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Using a modification on the procedure described in Part L of Example 2, 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol (8.50 g, 23.8 mmol) was treated with tert-butyl 2-iodoethylcarbamate (7.10 g, 26.2 mmol) and cesium carbonate (11.62 g, 35.67 mmol) in DMF (120 mL). During the workup, after the reaction mixture was concentrated under reduced pressure, the residue was treated with water (75 mL) and stirred for 30 minutes. A precipitate was isolated by filtration and washed with diethyl ether to yield 8.7 g of tert-butyl 2-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as an off-white solid, mp 152-153° C.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1.N>C(O)(=O)C.C(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:24][CH3:25])[CH:11]=2)=[O:9])[CH:3]=1
Reactant: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Agent: Br
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2)ccc1O
Reaction time: 3 h

Procedure:
ca) 50 ml of 33 percent hydrobromic acid in acetic acid are added dropwise within 15 minutes at 10° to 20 g of 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride. After stirring at 20° for 3 hours, the reaction mixture is poured into a mixture of 100 ml of conc. aqueous ammonia and ice. The pH is adjusted to 6 by adding acetic acid. The methylene chloride phase is separated: the aqueous phase is extracted twice more with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone of m.p. 150°-151°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH:14]=[O:15])([O-:11])=[O:10]>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([N+:9]([O-:11])=[O:10])=[C:13]([CH:14]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[OH:15])[CH:16]=1
Reactant: Clc1ccc(I)cn1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Temperature: -45 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.) in 10 mL anhyd. THF was stirred at −40° C. to −50° C. After five minutes, 2.2 mL of 2.1 MiPrMgBr/THF (4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the reaction mixture is maintained at −40 to −50° C. for 30 minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was then added and the reaction was maintained at −50° C. After 1 hour, the reaction was allowed to warm to −10° C., and quenched with 50 mL saturated brine after a further fifteen minutes. The crude product was extracted with EtOAc, dried on Na2SO4 and concentrated by rotary evaporation to yield desired product. MS: (M+H)/z=298.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](O)([C:11]([NH2:13])=[O:12])[C:6]=2[CH:15]=1.S(Cl)([Cl:18])=O>C(OCC)C>[Cl:18][C:7]1([C:11]([NH2:13])=[O:12])[C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: NC(=O)C1(O)CCOc2ccc(F)cc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: NC(=O)C1(Cl)CCOc2ccc(F)cc21
Temperature: 28 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 6-fluoro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-4-carboxamide (60 mg, 0.28 mmol) and thionylchloride (60 mg, 0.28 mmol) in 1.0 ml of diethyl ether was stirred for 5.0 hours at 28° C. The reaction mixture was evaporated in vacuo to give a pale yellowish oil which was chromatographed on silica gel, eluting with ethyl ether to give 43 mg (67.2%) of the desired refined compound.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.Cl.N[OH:18].[OH-].[Na+].O>C(O)(=O)C>[OH:18][NH:2][CH:4]=[N:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: CN(C)C=NC(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=Cc1ccccc1)N=CNO
Temperature: 5 °C
Yield: 89.4 %

Procedure:
N-[(Dimethylamino)methylene]-cinnamamide (1.0 g, 5.0 mmol) was added to a solution of hydroxylamine hydrochloride (415 mg, 6.0 mmol) in acetic acid (5 mL of 70% aqueous) and aqueous NaOH (1.2 mL, 5 M, 6.0 mmol). After stirring for 1.5 h water (5 mL) was added, and the reaction mixture was cooled to 5° C. in an ice bath. The solution was partitioned between ethyl acetate and water, and the organics were dried over Na2SO4, then concentrated in vacuo to afford N-[(hydroxyamino)methylene]-cinnamamide (850 mg, 90%). This material was carried on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=2[C:7]=1[OH:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:27]>C(OCC)(=O)C>[NH2:27]/[C:4](/[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1])=[C:6]1\[C:7](=[O:16])[C:8]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: N
Reactant: O=C(c1ccccc1Cl)c1sc2ccc(Cl)cc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccc(Cl)cc2C1=O)c1ccccc1Cl
Yield: 40 %

Procedure:
Prepared as in Example 1 from 2-(2-chlorobenzoyl)-5-chlorobenzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 40% of theory; m.p. 199°-201° C. (ethyl acetate).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>CO>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1
Reactant: Fc1ccccn1
Reactant: OC[C@H]1CCNC1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Yield: 58.4 %

Procedure:
(S)-Pyrrolidin-3-ylmethanol (9.89 mmol, 1 g), 2-fluoropyridine (29.7 mmol, 2.88 g) and triethylamine (49.4 mmol, 6.89 ml, 5.00 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. The resulting residue was purified by silica chromatography, eluting with DCM—5% MeOH/DCM to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methanol (1.03 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:76][CH:77]1[C:108](=[O:109])[N:79]2[C:80]([C:92]([O:94][CH:95]([C:102]3[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=3)[C:96]3[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=3)=[O:93])=[C:81](/[CH:84]=[CH:85]\[C:86]3[S:90][N:89]=[N:88][C:87]=3[CH3:91])[CH2:82][S:83][C@H:78]12>C1COCC1.C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:76][CH:77]2[C:108](=[O:109])[N:79]3[C:80]([C:92]([O:94][CH:95]([C:102]4[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=4)[C:96]4[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=4)=[O:93])=[C:81](/[CH:84]=[CH:85]\[C:86]4[S:90][N:89]=[N:88][C:87]=4[CH3:91])[CH2:82][S:83][C@H:78]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1.58 g, 2.35 mmol) was dissolved in a mixed solvent of THF-methylene chloride (20 ml-10 ml) and cooled to 5° C. HOBT (0.32 g, 2.4 mmol) was added to this reaction solution, then DCC (0.50 g, 2.4 mmol) was added and the mixture was stirred at the same temperature for 2 hours. The reaction solution was filtered, then benzhydryl 7-amino-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (0.98 g, 2.0 mmol) was added to the filtrate and it was stirred at 5° C. for 22 hours. The reaction solution was concentrated and then the concentrate was purified by column chromatography thereby benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (1.38 g, 60.5% yield) was obtained as a yellow powdered compound.
Reaction SMILES: [NH3:1].O=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1(C)C=CC=CC=1>[NH2:1]/[C:3](/[C:11]([F:14])([F:13])[F:12])=[C:4](/[F:10])\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)C(=O)C(F)(F)F
Reactant: N
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(F)=C(\N)C(F)(F)F

Procedure:
Ammonia is introduced with stirring into a solution of 7.5 g of ethyl 3-oxo-2,4,4,4-tetrafluorobutyrate in 20 ml of toluene at 75° C. up to saturation. Then the reaction mixture is heated using a water separator for 5 hours, during which ethyl 3-amino-2,4,4,4-tetrafluorocrotonate is formed as an intermediate.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[C:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])O)#[N:15].[Na]>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:19]([C:17]1[CH:16]=[C:14]([NH2:15])[N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[N:3]=1)=[O:20])[CH3:23]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC(=O)C(O)=CC#N
Agent: Cl
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(-c2cc(C(=O)O)ccc2C)n1
Yield: 84 %

Procedure:
To a solution of the above phenyl hydrazine intermediate, (50 mg, 0.247 mmol) in trifluoroacetic acid (TFA) (500 μL) was added sodium 2-cyano-1-ethoxycarbonyl-ethenol (49 mg, 0.298 mmol). The red mixture was heated to reflux for 2 h then cooled and concentrated. Purification by silica-gel chromatography (2% NH4OH/25% MeOH in EtOAc) provided 5-amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (60 mg, 83%) as a white solid: ESI MS m/z 290 [C14H15N3O4+H]+.