Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:13](O)[CH2:14][OH:15]>C(Cl)Cl>[O:1]1[CH2:13][CH2:14][O:15][C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:8][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[O:1]
Reactant: OCCO
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: ClCCl
Product: CC(=O)CC(=O)O
Product: COC(=O)CC1(CC(=O)OC)OCCO1
Temperature: 50 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of 4.2 g (24 mmol) of dimethyl 3-oxopentanedioate and 2.7 ml (48 mmol) of ethylene glycol in 50 mL of methylene chloride was added 12 mL (96 mmol) of TMSC1 at room temperature. The reaction mixture was stirred at 50° C. for 3 days. The reaction was quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel gave the desired product, dimethyl dioxolane-2,2-diyl)diacetate (2.6 g, 12 mmol, yield: 50%): MS (m/e): 219 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][OH:12].[ClH:13]>C(OCC)C>[ClH:13].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:12][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromo-3-methylbenzonitrile (15.0 g, 76.5 mmol) was dissolved in dry methanol (3.1 ml, 76.5 mmol) and dry diethyl ether (108 ml), cooled to 0-5°, then saturated with HCl (g). Stirred for 18 hours at room temperature and the solid collected by filtration, then dried in vacuo to yield the title compound as white needle-like crystals (19.3 g, 95%).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[C:15](OCCl)=[O:16].C(N(CC)CC)C.[CH:27]([Cl:30])(Cl)Cl>>[Cl:30][CH2:27][C:15]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:16]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(Cl)OCCl
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A mixture of dodecanol (10 g, 0.054 mol), chloromethyl chloroformate (6 g, 0.05 mol) and triethylamine (5.5 g) in 40 ml of dry chloroform was stirred at room temperature for 16 hours. The reaction mixture was then washed twice with water (50 ml per washing) and the organic phase was dried over anhydrous magnesium sulfate. Removal of the solvent gave 13.3 g (94% yield) of liquid product, which was chromatographed through a column of Florisil using chloroform as the eluent. 1HNMR(CCl4) δ0.90(3H, t, CH3); 1.28[20 H, s, broad, --(CH2)10 --]; 3.93(2H, s, --CH2Cl); 4.11 (2H, t, J=6Hz, --CH2 --O). νmax (film): 2940, 2880(CH); 1765, 1745(C=O); 1180 (--C--O--C--)cm-1.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12].O1CCC[CH2:21]1>>[CH3:21][O:13][C:11](=[O:12])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccnc1
Reactant: C1CCOC1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: [Na]
Product: COC(=O)C(Oc1cccnc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a slurry of 3-hydroxypyridine sodium salt, 4.6 g (26.4 mmol) in 200 mL of tetrahydrofuran was added 5.0 g (22.0 mmol) of alpha-bromophenylacetic acid. The reaction mixture was refluxed for two hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluent and concentrated to dryness to give 2.8 g of the desired mixture of isomers as a dark oil. MS (ion spray) 244.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:19]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1ccncc1
Reactant: Nc1nc[nH]n1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccncc2)nc2nc[nH]n12

Procedure:
Compound 7 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 4-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[O:1]1[C:5]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[Cl:19])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc2occc2c1
Product: Clc1ccc(Br)cc1Cc1cc2ccccc2o1

Procedure:
Benzo[b]furan and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2I)[CH2:3][CH2:2]1.C([Li])(C)(C)C.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:25]=[O:26])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: -78 °C
Yield: 94.1 %

Procedure:
1-(Cyclopropoxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 12; 5.84 g, 17 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to −78° C. Tert-butyl lithium solution (20 mL, 1.7M in pentanes, 34 mmol) was then added dropwise. The solution was stirred at −78° C. for 10 minutes, before N,N′-dimethylformamide (5.3 mL, 68 mmol) was added, and the resulting solution allowed to stir to room temperature. Saturated aqueous ammonium chloride solution (50 mL) was then added and the mixture extracted with diethyl ether (2×100 mL). The extracts were dried (MgSO4) and concentrated to yield an oil. Purification of this by silica chromatography gave the title compound as a clear oil (3.94 g, 16 mmol).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(Cl)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHCl3, 57.3 g (0.414 mol) of K2CO3 and 260 ml of water are placed in a one liter Erlenmeyer flask, 51.8 g (0.296 mol) of p-chlorobenzoyl chloride, dissolved in 50 ml of CHCl3, are added in the course of 15 minutes, whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with CHCl3 and the CHCl3 extract is washed with water until the pH is 6-7. It is dried over MgSO4, filtered and concentrated. The product is recrystallised from ethyl acetate.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([OH:29])[OH:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:28])[OH:29])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCCCP(O)O)OCc1ccccc1
Reactant: C=CCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.30 g of dodecene in 6 ml of dry toluene is heated to 80° under an atmosphere of argon. To this solution a suspension of 2.0 g of 3-benzyloxycarbonylaminopropylphosphonous acid in 30 ml of dry toluene containing 0.6 g of t-butylcyclohexylperdicarbonate is added within 15 minutes. The reaction mixture is then stirred at 80° for 2 hours. An additional amount of 0.6 g of the radical initiator is added and stirring at 80° is continued for 2 hours. Then, the reaction mixture is cooled to room temperature and the solvent is removed by means of a rotary evaporator. The residue is triturated with petroleum ether (60°-80°), filtered and dried to give 3-benzyloxycarbonylaminopropyl(dodecyl)phosphinic acid as a white solid, m.p. 115°-6°; 31P-NMR: δ=+58.7 ppm (CDCl3).
Reaction SMILES: S(Cl)([Cl:3])=O.CO[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=O)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=1.[Na+].CN(C)[CH:24]=[O:25]>>[Cl:3][S:13]([C:10]1[CH:11]=[C:12]([O:25][CH3:24])[CH:7]=[CH:8][C:9]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:15])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(OC)ccc1S(=O)(=O)[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 500 ml of thionyl chloride was added portionwise over 1 hour 100 g of the compound of Example 3. The reaction mixture was stirred 0.5 hours, and 5 ml of dimethylformamide was added over 1 hour. The mixture was refluxed overnight. The orange solution was cooled to ambient temperature and concentrated in vacuo to a yellow semisolid. The reaction product was dissolved in 250 ml dichloromethane, and the solution was concentrated in vacuo. The resulting solid was partitioned between ether and water. The organic phase was washed with water, twice with aqeous sodium bicarbonate, dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 47 g of the title compound, m.p. 69°-72° C.
Reaction SMILES: C[O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.ClCC(O)=O.[O-:23][C:24]#[N:25].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:24]([NH2:25])=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:3](=[O:2])[CH2:4][C:5]=2[CH:6]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 40 °C
Yield: 24.8 %

Procedure:
A mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 106 gms of monochloro-acetic acid and 73 gms of sodium cyanate were heated to 40° C. under stirring and maintained for 4 hours. After completion of the reaction (monitored by HPLC and/or TLC), the mixture was cooled to room temperature, filtered and washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid, and the mixture was heated to 75-80° C. and maintained for 2 hours under good agitation. It was then cooled to 0-5° C. and maintained for 2 hours, and the product oxcarbazepine was separated by filtration. This was then purified twice in toluene:methanol followed by methanol:dichloromethane solvent mixture to furnish 28 gms of pure oxcarbazepine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C>C(O)C>[CH2:4]1[C:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:2][CH2:3]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21

Procedure:
A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equiv) and decolorizing charcoal (0.5 g) in absolute ethanol was heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, charcoal was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum and diluted with water (20 mL). It was then extracted by EtOAc (3×30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent and recrystallization from DCM-Hexane gave the title compound (1.17 g). 1H-NMR (CDCl3): δ 10.49 (1 H, br s), 7.79 (1H, d), 7.43 (1H, d), 7.43 (1H, d), 7.06 (2H, m), 5.27 (1H, br s), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 (3H, t); MS (ES): 257 (MH+).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH2:14]([O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][C@@H:30]([OH:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=1[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=4[C:46]=3[NH:45][C:44]2=[O:56])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:56]=[C:44]1[N:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:2]([O:35][C@@H:30]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][C:25]3[CH:24]=[C:23]([CH3:36])[C:22]([O:21][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:27]([CH3:28])[CH:26]=3)=[O:3])[CH2:42][CH2:41]2)[C:47]2[CH:48]=[N:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[C:46]=2[NH:45]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 1.28 g (6.36 mmol) 4-nitrophenyl chloroformate were added at RT to a solution of 0.78 g (6.36 mmol) 4-dimethylaminopyridine in 100 mL pyridine and the mixture was stirred for 1 h at RT. Then a solution of 2.00 g (6.36 mmol) methyl(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate in 20 mL pyridine was added dropwise at RT and the reaction mixture was stirred for 2 h after the end of the addition. Then 1.71 g (6.36 mmol) 3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinoline-2-one was added to the reaction mixture, which was then heated to 100° C. for 4 h. The precipitate formed was filtered off, the filtrate was evaporated down i.vac., the residue was mixed with 200 mL EtOAc and 200 mL semisaturated KHSO4 solution, the product being obtained as a precipitate. This was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([OH:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:27]=[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10])[C:18]2=[O:20]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1F
Reactant: Oc1ccc(Cl)c(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccccc2F)coc2cc(O)c(Cl)cc12

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (1.889, 13.0 mmol), 2-fluorophenylacetic acid (2.0 g, 13 mmol), BF3Et2O (10 ml), PCl5 (4.0 g, 19.2 mmol), DMF (20 ml and 10 ml). The pale white precipitate formed was shown to contain the required compound and was taken directly onto the next stage.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:26]=2[CH:27]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=4)[C:29]3=[O:37])[C:26]=2[CH:27]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, 5,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (29%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=4.1 Hz, 1H), 7.71 (ddd, J=9.4, 7.7, 1.7 Hz, 1H), 7.31-7.22 (m, 3H), 7.15 (dd, J=7.4, 0.9 Hz, 1H), 7.05 (ddd, J=8.4, 7.5, 0.9 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.79 (dd, J=10.3, 6.3 Hz, 1H), 6.66 (dd, J=9.2, 7.9 Hz, 1H), 5.23 (d, J=15.9 Hz, 1H), 5.06-4.96 (m, 2H), 4.77 (d, J=9.1 Hz, 1H); MS (ES+) m/z 365.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:45][N:44]1[C:40]([C:38]([NH:37][C:35]2[CH:36]=[C:31]([O:30][C:27]3[CH:28]=[CH:29][C:24]4[N:25]([CH:48]=[C:22]([NH:21][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:23]=4)[N:26]=3)[CH:32]=[CH:33][C:34]=2[CH3:47])=[O:39])=[CH:41][C:42]([CH3:46])=[N:43]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CS(C)(=O)=O)cn4n3)ccc2C)n(C)n1
Yield: 38.1 %

Procedure:
In the same manner as in Example 279 and using (methylsulfonyl)acetic acid (100 mg, 0.73 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (63 μL, 0.73 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (91 mg, 38%) was obtained as a pale-yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=1[OH:27]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:17]=1[O:27][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: Oc1ccc(OC(F)(F)F)cc1Cl
Product: O=c1cc(Oc2ccc(OC(F)(F)F)cc2Cl)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-4-trifluoromethoxy-phenol afforded 5-(2-chloro-4-trifluoromethoxy-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) afforded 2-[4-(2-chloro-4-trifluoromethoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid as a white solid (190 mg, 72% for the final step); ES+-HRMS m/e calcd for C20H20N2O5F3Cl [M+H+] 461.1086, found 461.1085. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74-1.28 (m, 5H), 1.35-1.80 (m, 6H), 1.80-1.96 (m, 1H), 1.98-2.11 (m, 1H), 5.40 (dd, J=10.9, 4.2 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 7.54 (dd, J=9.0, 2.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 13.03 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[CH:29]=[C:30](I)[S:31][C:24]=12)[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][CH2:41]CO>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:17]1[CH:19]=[CH:20][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[CH:29]=[C:30]([C:8]4[CH:9]=[CH:10][C:5]([C:3]([O:2][CH2:1][CH2:39][O:40][CH3:41])=[O:4])=[CH:6][CH:7]=4)[S:31][C:24]=23)=[C:15]([F:14])[CH:16]=1
Reactant: COCCO
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COCCOC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Temperature: 85 °C

Procedure:
A round-bottomed flask was charged with 4-(methoxycarbonyl)phenylboronic acid (0.472 g, 2.62 mmol), 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.750 g, 1.94 mmol), cesium carbonate (0.949 g, 2.91 mmol), and 2-methoxyethanol (10 mL). The mixture was purged with nitrogen for 10 minutes and then Pd(PPh3)4 (0.135 g, 0.117 mmol) was added. The mixture was heated under nitrogen to 85° C. for 18 hours and then cooled to room temperature. The mixture was diluted with water (30 mL) and the resulting precipitate collected by filtration. After drying under high vacuum, the product was isolated (0.26 mg, 25%) as an off-white solid. LRMS (esi+) 439 m/z (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH:39](Br)[CH3:40])(=[O:37])[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:39]([O:38][C:35](=[O:37])[CH3:36])[CH3:40])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (190 mg, 0.45 mmole) and potassium carbonate (75 mg, 0.54 mmole) in DMF (5 ml) was added at 5° C. 1-bromoethyl acetate** (90 mg, 0.54 mmole). The mixture was stirred at 5° C. for 1.5 hours and diluted with ethyl acetate (20 ml). The dilute was washed successively with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (5 g) with 1% methanol in chloroform. The desired fractions were combined and concentrated. The residue was dissolved in dioxane and lyophilized to yield 103 mg (45%) of the title compound as its dioxane solvate. Mp. 105°-110° C. Estimated purity 85% (by HPLC).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[C:7]([O:13][CH2:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:16].[K+].C(O)C.[OH2:21]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:21])=[O:16])=[C:7]([O:13][CH2:14][CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CCOc1nc(C(C)(C)C)ccc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCOc1nc(C(C)(C)C)ccc1C(=O)O
Temperature: 90 °C
Yield: 95 %

Procedure:
6-tert-Butyl-2-ethoxy-nicotinonitrile (1.10 g, 5.3 mmol, prepared according to the literature procedure by Youngdale, G. A. and T. F. Oglia J. Med. Chem. 1985, 28, 1791) and potassium hydroxide (1.80 g, 32.3 mmol) were combined in ethanol/water (30 ml/7 ml) and heated at 90° C. overnight. The reaction was concentrated, acidified with 2N hydrochloric acid solution (20 ml) and extracted with chloroform. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated to give 6-tert-butyl-2-ethoxy-nicotinic acid as a white solid (1.00 g, 95%) LR-MS: 222 [(M−H)+]