Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH:18]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH:18]1([C:21]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1
Reactant: c1cc(C2CC2)nc(N2CCNCC2)c1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(C5CC5)n4)CC3)nc2N1
Reaction time: 0.33 h

Procedure:
A mixture of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.47 g, 2.0 mmol) and 1-(6-cyclopropyl-pyridin-2-yl)-piperazine (0.41 g, 2.0 mmol) in dichloroethane (12 mL) was stirred for 20 min and NaBH(OAc)3 (0.55 g, 2.6 mmol) was added. The reaction was stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by liquid chromatography (Biotage 12M, eluted with CHCl3) gave the title compound as an oil. The oil was dissolved in Et2O and treated with anhydrous HCl gas to give a precipitate. The mixture was filtered, washed with Et2O and hexanes and dried to give a white solid (121 mg). MS: APCI: M+1: 422.3 (Exact Mass: 421.25).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.Br[C:23]1C=C(Cl)C=C(Cl)[C:24]=1[CH2:31]Br.C1(=O)NC(=O)C2=CC=CC=C12.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CC#N>[Cl:21][C:16]1[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([CH:31]2[CH2:24][CH2:23]2)[C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1c(Cl)cc(Cl)cc1Br
Reactant: Clc1cc(Cl)c(CBr)c(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=C1NC(=O)c2ccccc21
Solvent: CC#N
Product: NCc1c(Cl)cc(Cl)cc1C1CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A.2.1.1. Synthesis of 2-(2-bromo-4,6-dichlorobenzyl)isoindoline-1,3-dione To a soln. of 1-bromo-2-(bromomethyl)-3,5-dichlorobenzene (1.98 mmol) [J. Med. Chem. 1992, 35, 4221-4229] in 10 mL CH3CN were added phthalimide (1.98 mmol) and K2CO3 (5.93 mmol). The reaction mixture was stirred at 50° C. for 6 h and then at RT overnight. Sat. aq. NaHCO3 soln. was added and the mixture was extracted 3 times with DCM. The comb. org. phases were dried over MgSO4 and conc. in vacuo to obtain the desired product as beige solid.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)(C)C.I[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH2:34]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CI
Reactant: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Isopropyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Iodo-2-methyl-propane provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (m, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1 H), 7.83 (d, J=6.6 Hz, 1 H), 7.73 (t, J=6.6 Hz, 1H), 7.54 (s,1H), 7.52 (m, 1H), 7.38 (d, J=9.1 Hz, 2 H), 7.15 (m, 2H), 7.00 (d, J=8.7 Hz, 2 H), 5.38 (s, 2H) 3.93 (d, J=7.5 Hz, 2 H), 4.29 (m, 1H), 0.95 (d, J=6.6 Hz, 6H); MS: (M+H m/z=435.2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[CH3:13][N:14](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(I)nc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C#N)nc1Cl
Temperature: 100 °C
Yield: 88 %

Procedure:
2-Chloro-6-iodo-3-isopropoxy-pyridine (2.00 g, 6.722 mmol) was dissolved in DMF (15 mL). Zn(CN)2 (592 mg, 5.04 mmol) was added, and the mixture was bubbled with nitrogen gas prior to the addition of Pd(PPh3)4 (600 mg, 0.519 mmol). The reaction system was sealed and heated under microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous sodium bicarbonate solution (75 mL) followed by brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a clear oil which was purified by silica gel column chromatography: 0-30% EtOAc/hexane gradient to provide 6-chloro-5-isopropoxy-pyridine-2-carbonitrile (1.17 g, 88%) as a clear colourless oil that crystallized upon standing. ESI-MS m/z calc. 196.0, found 197.3 (M+1)+; Retention time: 1.46 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.67 (dt, J=12.1, 6.1 Hz, 1H), 1.45 (d, J=6.1 Hz, 6H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(C(=O)C2CC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1ccnc(OC)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.99 g) in THF (200 ml) was added ethyl diethylphosphonoacetate (29.7 mL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the obtained colorless solution was added cyclopropyl(2-methoxypyridin-4-yl)methanone (4.42 g) at 0° C., and the mixture was heated under reflux for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH2:25])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH:25][C:27](=[O:29])[CH3:28])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc3nc(N)sc3n2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-fluorophenyl}carbamate (0.94 g, 2.5 mmol) and N,N-dimethylpyridine-4-amine (0.31 g, 2.5 mmol) in pyridine (5 mL) was added dropwise acetyl chloride (0.40 g, 5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (1.05 g, quantitatively) as a white amorphous.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].Cl.[CH3:31][O:32][NH2:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2[NH:33][O:32][CH3:31])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (3.71 mmol) in dry tetrahydrofuran (60ml) was mixed with O-methyl hydroxylamine hydrochloride (37.1 mmol) and triethylamine (6.2 mL). The mixture was stirred at room temperature for 96 hours under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue chromatographed on a flash silica gel column eluting with CHCl3—CH3OH (99:1), to give (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolan-3-yl acetate, a compound of formula (4), which was crystallized from a mixture of chloroform/hexanes (1:1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.[BrH:22]>>[BrH:22].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: CCCN1CCCC(c2ccc(OC)c3c2CC(=O)N3)C1
Agent: Br
Product: CCCN1CCCC(c2ccc(O)c3c2CC(=O)N3)C1

Procedure:
1.55 g of the product of Example 2 in 15 ml of 48% hydrobromic acid were refluxed for 2 hours with stirring under an inert atmosphere. After evaporating to dryness under reduced pressure, crystallizing the oil obtained from ethanol, filtering, washing with ether, drying, and purifying by crystallization from methanol, 1.31 g of 1,3-dihydro-7-hydroxy-4-(1-propyl-3-piperidinyl)-2H-indol-2-one hydrobromide melting at 210° C. were obtained.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:11]/O)/[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1
Reactant: O/N=C1\CCOc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of (4E)-2,3-dihydro-4H-chromen-4-one oxime (3.20 g) in tetrahydrofuran (50 ml) under N2 atmosphere was added lithium aluminum hydride (1M THF, 50 ml). The reaction mixture stirred at ambient temperature for 16 h and was quenched with 10 ml of water, 10 ml of 2 N NaOH and 20 ml of water. The reaction mixture was filtered through celite, acidified with 1 N HCl (50 ml), washed with ethyl ether (2×50 ml), basified with 2 N NaOH, extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC was run on a biotage 40S column with 2-4% methanol/methylene chloride with 0.5% ammonium hydroxide to provide the title compound as an oil (728 mg, 25%): 1H NMR (300 MHz, CDCl3) δ) 7.34, 7.17, 6.92, 6.85, 4.31-4.24, 4.09, 2.18, 1.91-1.86; HRMS (FAB) calcd for C9H11NO+H 150.0919, found 150.0910.
Reaction SMILES: [C:1]([O:5][CH:6]([O:8][CH2:9][CH3:10])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:11]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:21]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23].N(C(C)(CC)C([O-])=O)=N[C:36](C)(CC)C([O-])=O>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:5][CH:6]([O:8][CH2:9][CH3:10])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:11]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:21]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23].[C:11]([O:16][CH:17]([CH3:36])[CH2:18][O:20][CH3:19])(=[O:15])[CH3:12]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OCC1CO1
Agent: C=C(C)C(=O)OCc1ccccc1
Agent: C=CC(=O)OC(C)OCC
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 43.3 g (0.3 mol) of 1-ethoxyethyl acrylate, 25.6 g (0.18 mol) of glycidyl methacrylate, 21.2 g (0.12 mol) of benzyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in propylene glycol monomethyl ether acetate, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A-4 (1-ethoxyethyl acrylate/glycidyl methacrylate/benzyl methacrylate) as a propylene glycol monomethyl ether acetate solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:4][C:3]=1[O:26][CH3:27].[C:28]([O-])([O-])=O.[K+].[K+].COS(=O)(=O)OC>CC(C)=O.O>[CH3:27][O:26][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OC)c(OC)c2)ccc1O
Yield: 44.5 %

Procedure:
To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (368 mg, 1.0 mmol, 1.0 eq.) in dry acetone (10 mL) were added anhydrous K2CO3 (138 mg, 1.0 mmol, 1.0 eq.) and sulfuric acid dimethyl ester (176 mg, 1.0 mmol, 1.0 eq.) at rt. The reaction mixture was heated under reflux overnight, cooled, diluted with water and extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with H2O, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by silica column chromatography using CH2Cl2 as eluent to provide (1E,6E)-1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (170 mg, 44%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:30]1
Reactant: Clc1ccccc1CC1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.2 mg). Calcd for C22H18ClF3N2O2: 434.1009, found 434.1000.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]2[CH2:12][C:13](=[CH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)([OH:30])[CH2:26][CH2:25]3)[C:14]3[C:15]([O:20][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[N:16][CH:17]=[CH:18][CH:19]=3)(O)=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:50][N:51](C)[CH2:52]CCN=C=NCC.Cl.CNC>CN(C)C=O.C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:27]2([OH:30])[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][CH:21]=[C:13]3[C:14]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[O:20][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:4][C:1]([N:51]([CH3:52])[CH3:50])=[O:2])[C:11]=4[CH2:12]3)[CH2:25][CH2:26]2)=[CH:36][CH:35]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of product of example 133 (420 mg) in dimethylformamide (17 ml) were added 1-hydroxybenzotriazol hydrate (250 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (310 mg), dimethylamine hydrochloride (270 mg) and triethylamine (0.45 ml), and the mixture stirred at room temperature for 12 hours. Water and chloroform were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give the titled compound (380 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2c1NCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2c1NCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 8-fluoro-5-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (290 mg, 1.463 mmol) in EtOAc (15 mL) was added a slurry of 10% Pd/C (50 mg) in IMS (2 mL) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording the title compound as purple oil (243 mg, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[CH2:2].[CH3:12][C@@H:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OC1C=CC(C(O)=O)=CC=1)C=C.C1([C@@H](N)C)C2C(=CC=CC=2)C=CC=1>>[CH3:12][C@@H:13]([NH:20][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: C[C@@H](N)c1ccccc1
Agent: C=CCOc1ccc(C(=O)O)cc1
Agent: C[C@H](N)c1cccc2ccccc12
Product: C=Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1

Procedure:
(R)-N-α-Methylbenzyl-4-vinylbenzamide was prepared as above in Example 1 except 2.5 g (0.017 mole) of 4-vinylbenzoic acid and 2.13 g (0.018 mole) of (R)-α-methylbenzylamine (Aldrich) were used rather than the 2.0 g of 4-allyloxybenzoic acid and 2 g of (S)-1-(1-naphthyl)ethylamine in Example 1. The product was recrystallized from absolute ethanol to give 1.85 g (44%) of white crystals; mp 162°-163° C.; [α]D25 -25.49° (c=0.404, CHCl3); IR (KBr): 3390 and 1640 cm-1 ; NMR (δ): 1.64 (3H, d, J=7.4 Hz); 5.32 (1H, q, J=7.4 Hz); 5.44-5.94 (2H, m); 6.48-6.92 (2H, m), 7.24-7.82 (9H, m). Anal. for C17H17NO: Calcd: C, 81.27; H, 6.77. Found: C, 81.24; H, 6.79.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[CH:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47](O)=[O:48])[N:45]=1)=[O:39].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.O.CN(C)C=O>[CH:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47]([NH:2][CH:3]2[C:28](=[O:29])[N:5]3[C:6]([C:12]([O:14][CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]23)=[O:48])[N:45]=1)=[O:39]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Yield: 89.8 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (1.9 g) and trimethylsilylacetamide (4.6 g) in ethyl acetate (30 ml) was added at -30° C. a solution of the activated acid, which was prepared by stirring a mixture of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.1 g), phosphorus oxychloride (0.81 g), N,N-dimethylformamide (0.39 g) and ethyl acetate (20 ml) for half an hour under ice-cooling, and the mixture was stirred at -30° to -10° C. for an hour. After addition of ethyl acetate (100 ml) and water (50 ml), the organic layer was separated out, washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:18][N:19]2[C:24]=1[C:23]([CH3:25])=[N:22][N:21]=[C:20]2[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:18][N:19]2[C:24]=1[C:23]([CH3:25])=[N:22][N:21]=[C:20]2[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cnccn4)nnc(C)c3c2-c2ccccc2F)cc1
Product: Cc1nnc(-c2cnccn2)n2nc(OCc3ncnn3C)c(-c3ccccc3F)c12

Procedure:
This compound was prepared using the procedure described in example 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as described in EP-A-170073) instead of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonic acid 3-(2-fluorophenyl)-4-methyl-7-(pyrazin-2-yl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester instead of toluene-4-sulfonic acid 3-tert-butyl-7-(2,6-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester. Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 2.54 (3H, s), 3.84 (3H, s), 5.54 (1H, d, J=13 Hz), 5.58 (1H, d, J=13 Hz), 7.21 (1H, m), 7.26 (1H, m), 7.36 (1H, td, J=7.4, 1.8 Hz), 7.46 (1H, m), 7.84 (1H, s), 8.85 (2H, m), 9.48 (1H, d, J=1.4 Hz); MS (ES+) m/e 418 [MH]+. Anal. Found C, 57.37; H, 3.73; N, 28.99%. C20H16FN9O.0.3 H2O.0.07 C6H14 requires C, 57.19; H, 4.13; N, 29.40%.