Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][O:35][C:34]1=[O:38]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][O:35][C:34]5=[O:38])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C1OCCN1CCO
Product: O=C1OCCN1CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-(2-hydroxyethyl)1,3-oxazolidin-2-one following General Procedure J.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]1([S-:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CC(O)C.O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: [S-]c1ccccc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-amino-3-nitro-6-(phenylmercapto)pyridine was prepared by heating 2-amino-6-chloro-3-nitropyridine (84.0 g, 0.484 mol) and sodium thiophenolate (Fluka) (72.0 g, 0.545 mol) in 2-propanol (1500 mL) under reflux for 2 hours. After cooling to room temperature the suspension was diluted with water (100 ml), the solid was collected by vacuum filtration, washed with water and 2-propanol, and dried at 50° C. under vacuum to give 109.1 g (95% yield) of 2-amino-3-nitro-6-(phenylmercapto)pyridine, m.p. 148-152° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)[CH2:10][O:9]2)=[N:6][CH:7]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)([OH:9])[CH2:10][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(C2(c3ccc(Cl)cn3)CO2)nc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cn1
Temperature: 85 °C
Yield: 47.7 %

Procedure:
2,2-Bis(5-chloro-pyrid-2-yl)oxirane (0.8 g), 1,2,4-triazole (1.0 g) and anhydrous potassium carbonate (3.0 g) were stirred in dry N,N-dimethylformamide (30 ml) and the mixture was heated at 85° C. for 1.5 hours. The solvent was then evaporated under vacuum, with the addition of xylene to remove final traces of N,N-dimethylformamide as an azeotrope, and the residue was dissolved in water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over megnesium sulfate and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate. Evaporation of the relevant fractions gave a viscous oil which solidified on trituration with petroleum ether (b.p. 60°-80° C.). Recrystallization from hexane gave the title compound as white crystals (0.48 g, 38%) m.p. 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[Br:27]Br.O>C(O)(=O)C>[Br:27][C:3]1[C:4]([OH:26])=[C:5]([CH:24]=[O:25])[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)c(Br)c(O)c(C=O)c1O2
Temperature: 25 °C

Procedure:
To a solution of psoromic acid (1 mmol) in glacial acetic acid (5 ml) was dropwise added a solution of bromine (3 mmol, 0.15 ml) in glacial acetic acid (3 ml). After stirring at room temperature for several hours, the redbrown reaction mixture was poured into water (50 ml), extracted with ethyl acetate (100 ml), dried with MgSO4, filtered, and evaporated by a rotatory evaporator to give a redbrown solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH3:33][CH2:34][N:35](C(C)C)C(C)C.C(N)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:35][CH2:34][CH3:33])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Agent: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCCl)cc3c2=O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A suspension of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (425 mg) in methylene chloride (8 ml) was cooled to 0° C. and oxalyl chloride (0.2 ml) was added followed by DMF (10 μL) and the reaction mixture was left to stir at room temperature for 1 hour when N,N′-diisopropylethylamine (0.8 ml) and ethylamine (2.28 ml of a 2.0M in THF) were added. The reaction mixture was stirred at room temperature for 17 hours and concentrated. The residue was diluted with ethyl acetate and washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown foam which was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to ethyl acetate to give 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a pale yellow solid (323 mg); NMR Spectrum: (DMSOd6) 1.11 (t, 3H), 2.11 (s, 3H), 2.27 (s, 3H), 3.28 (m, 2H), 4.01 (t, 2H), 4.41 (m, 2H), 7.13 (s, 1H), 7.52 (m, 2H), 7.73-7.78 (m, 3H), 7.89 (d, 1H), 8.50 (t, 1H); Mass Spectrum: M+H+ 399.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[ClH:24].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(C(N)=O)cc1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CCCCCC.[Cl:19][C:20](=[CH2:29])[CH2:21][CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24].C(I)C>C1COCC1>[Cl:19][C:20](=[CH2:29])[CH2:21][C:22]([CH2:1][CH3:2])([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)NC(C)C
Reactant: C=C(Cl)CC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCI
Product: C=C(Cl)CC(CC)(CC)C(=O)OC
Reaction time: 0.75 h

Procedure:
To a cold solution (0° C.) of diisopropylamine (0.80 mL, 5.7 mmol) in THF (5 mL) was added a 1.6M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) over a 5 minute period and stirring was continued for an additional 45 min. Then a solution of methyl 4-chloro-2-ethyl-4-pentenoate (800 mg, 5 mmol) from Example 27, Step A, in THF (2 mL) was added and the reaction was stirred at 0° C. for another 30 minutes. Then ethyl iodide (440 μL, 5.5 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with NH4OAc buffer (50 mL of 25% w/v) and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude product was purified by Kugelrohr distillation (b.p. 120° C. at 0.1 mm Hg) to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][C:16]2(S(C)=O)[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:31])[C:4]1=[O:32])[CH3:2].[NH3:33]>O1CCOCC1>[NH2:33][C:16]1([NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:32])[C:5]2=[O:31])=[O:10])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]([CH3:20])[NH:18][C:17]1=[O:21]
Reactant: N
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)NC(C(=O)NC2(N)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The sulphoxide (61) (145 mg) in dioxan (5 ml) was treated with ammonia (21 ml) overnight at room temperature. The solvent was then evaporated and the residue chromatographed on silica gel to give the product (62) as a white solid (95 mg), νmax. (CHCl3) 3400, 3280, 1770, 1715 and 1690 cm-1, δ(CDCl3) 0.87, 0.90, 1.10 and 1.14 (each d, J6 Hz, together 3H), 1.20 (t, J7 Hz, 3H), 1.6-2.9 br (2H, exch.), 3.40-3.65 (m, 4H) (irradiation at 0.90 caused this signal to simplify), 3.85 (2×q, J7 Hz, together 1H) (irradiation at 0.87 or 1.10 caused one of the above signals to collapse to a s), 3.95-4.13(m, 2H), 5.45(2×d, J7 Hz, together 1H, collapses to 2×s on exch), 6.50, 6.58, 6.63, and 6.72 br (each s, together 1H, exch.), 7.25-7.56 (m, 5H), 7.62, 7.76, 7.90, and 8.06 br (each s, 1H, exch.), and 9.90 (2×d, J7 Hz, together 1H, exch.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([NH:29][CH2:30][CH2:31][NH2:32])[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([NH:32][CH2:31][CH2:30][NH:29][C:22]2[N:21]=[C:20]([NH2:19])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)[CH:14]=1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene (20 mgs, 0.06 mmol) in N,N-dimethylformamide was added 2-amino-3-nitro-6-(2-aminoethylamino)pyridine (14 mgs, 0.07 mmol) and N,N-diisopropylethyl amine (16 μl, 0.07 mmol) and heated to 80° C. over-night. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and concentrated. Purification on silica gel with 5% methanol in dichloromethane as eluent yielded 7 mgs of N˜6˜-{2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)amino] ethyl}-3-nitropyridine-2,6-diamine.
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17](=O)[CH3:18])=[CH:15][C:10]=2[CH2:9][CH2:8][N:7]([C:20]([O-:22])=[O:21])[CH2:6]1)(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+].[C:56]1([CH3:62])[CH:61]=CC=C[CH:57]=1>>[C:17]([NH:16][C:14]1[CH:13]=[CH:12][C:11]2[CH2:5][CH2:6][N:7]([C:20]([O:22][C:56]([CH3:62])([CH3:61])[CH3:57])=[O:21])[CH2:8][CH2:9][C:10]=2[CH:15]=1)(=[S:32])[CH3:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)CCN(C(=O)[O-])CC2C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=S)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
1,1-dimethylethyl-7-(acetylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (818 mg) and Lawesson's reagent (1.1 g) were combined in toluene (10 ml) and refluxed for 1.5 h. After cooling the reaction was worked up with ethyl acetate/NaHCO3 (sat. sol.). The combined organic layers were concentrated and the residue was purified by flash chromatography over silica gel, eluting with 40% ethyl acetate in hexane, affording the title compound (411 mg).
Reaction SMILES: [Cl:1][SiH:2](Cl)[CH:3]=[CH:4]C.[CH2:7]([Mg]Cl)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(Cl)(Cl)=O.[SiH3]O.Cl[SiH3].[CH2:35]1COCC1>CCCCCC>[CH2:7]([Si:2]([CH:3]=[CH2:4])([CH3:35])[Cl:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: CC=C[SiH](Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Cl
Agent: O[SiH3]
Agent: [SiH3]Cl
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: C=C[Si](C)(Cl)CCCCCCCCCCCCCCCCCC
Reaction time: 8 h

Procedure:
(Me2N--SiMeC18H37)--CH2CH2 --(C8H17 --SiMe--NMe2) was prepared as follows. Dichloro-methylvinylsilane (92 grams, 0.8 moles, from the Aldrich Chemical Co., Milwaukee, Wis., USA) and 250 mL of tetrahydrofaran (THF) were added to a reaction flask. A 1M solution of octadecylmagnesium chloride (800 mL) in THF (from Aldrich Chemical Co.) was added portionwise over about 1.5 hours with stirring and cooling to 0° to 10°. The resulting dark mixture warmed to 26° during the next 30 minutes. Hexane was added (2 L), and the resulting solid was filtered off. The volatiles were removed from the filtrate on a rotary evaporator, and hexane was added to the residue. The solid was filtered off, and the volatiles removed from the filtrate again to yield an oil. Thionyl chloride (12 mL) was added to the oil to convert any silanol to chlorosilane. This solution was heated to 45° and allowed to stand overnight at ambient temperature. After removal of volatiles, the resulting black mixture was vacuum distilled, providing a 134-g fraction of octadecyl vinyl methylchlorosilane (compound A), as a clear, colorless oil with a boiling point of 170°-183°/0.1 mm. Gas chromatography/mass spectrometry (GC/MS) showed the product to be 87% octadecyl vinyl methylchlorosilane and 10% octadecyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[C:15](O)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[C:47]1([CH:53]([O:60][C:61]([C:63]2[N:68]3[C:69](=[O:72])[C@@H:70]([NH2:71])[C@H:67]3[S:66][CH2:65][C:64]=2[O:73][S:74]([CH3:77])(=[O:76])=[O:75])=[O:62])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[C:47]1([CH:53]([O:60][C:61]([C:63]2[N:68]3[C:69](=[O:72])[C@@H:70]([NH:71][C:15](=[O:16])/[C:14](/[C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[S:10][CH:11]=4)=[N:18]\[O:19][C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:67]3[S:66][CH2:65][C:64]=2[O:73][S:74]([CH3:77])(=[O:76])=[O:75])=[O:62])[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 0.6 %

Procedure:
To a suspension of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (41.7 g : 78.8 mMol.) in dichloromethane (600 ml) is added at -30° C. N-methylmorpholine (7.575 g : 75 mMol.), and the mixture is stirred for 10 minutes, mixed with 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (37.27 g : 75 mMol.), is stirred at the same temperature for 50 minutes, mixed with 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (14.38 g : 75 mMol.), stirred under ice cooling for 3 hours, diluted with water, and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene containing 0.5% acetic acid : ethyl acetate=10:1) and the eluate is treated with etherhexane to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)- 2-trityloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (57 .42 g). Colorless powder. Yield: 79%. This product contains ca. 5% of the 2-cephem isomer.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C[Si](Cl)(C)C>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Ic1ccc(I)cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was stirred for 3 hours. To the mixture was added TMSCl (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Cl:8])[C:3]=1[Cl:9]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
A mixture of 9.0 kg of 1,2,3-trichlorobenzene in 13.32 L of concentrated sulfuric acid is acid by drops to a solution of 4.13 L of 70% nitric acid and 4.13 L of concentrated sulfuric acid at 25-30° C. The slurry is stirred for 1.5-2 hours, then poured over 35 kg of ice and filtered. The filter cake is washed (15 L water) and then dissolved in 58 L of ethyl acetate. The organic phase is washed with water, aqueous sodium bicarbonate solution, and aqueous sodium chloride solution. The solution is dried over magnesium sulfate and concentrated to give the title product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([NH:15][CH2:16][C:17]2[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
3.47 g of benzyl bromide is added dropwise to a mixture of 6 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride, 3.24 g of potassium carbonate and 90 ml of dimethylformamide, and the resulting mixture is stirred at 60° C. for 3 hours. The reaction mixture is poured into 300 ml of ice-water and is extracted three times with 100 ml of ethyl acetate and twice with 50 ml of the same. The extract is washed with a saturated aqueous solution of sodium chloride and then dried. The solvent is distilled off from the dried extract, and the residue (7.5 g) is purified by column chromatography with 150 g of silica gel, using chloroform as a developer, to give 5.7 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate. The product is dissolved in 100 ml of ether, and dried hydrogen chloride gas is introduced into the solution. The resulting crystals are collected by filtration and recrystallized from isopropyl alcohl to give 4.3 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate hydrochloride, mp 137° to 141° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]([CH2:33][CH2:34][C:35]4[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=4)[NH:24][N:25]=3)=[O:16])=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)=O)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 0.9 %

Procedure:
4-(4-acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from methyl 4-(4-acetylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol ), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 31-51% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (3 mg, 1.0%); 1H NMR (399.9 MHz, DMSO-d6) δ 2.06 (3H, s), 2.78 (4H, s), 3.28 (2H,s) 3.25 (2H, t), 3.49-3.56(4H, m), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.99 (2H, d), 7.92 (2H, d), 10.32 (1H, s), 12.08 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([C:33]3[S:37][C:36]([CH3:38])=[N:35][CH:34]=3)[NH:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:6]=2[CH:39]=1.CC(O)C.Cl>C(Cl)(Cl)Cl.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([C:33]3[S:37][C:36]([CH3:38])=[N:35][CH:34]=3)[NH2:13])[C:6]=2[CH:39]=1
Reactant: Cc1ncc(C(COc2noc3ccc(Cl)cc23)NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1ncc(C(N)COc2noc3ccc(Cl)cc23)s1

Procedure:
To a solution of 1.7 g of 5-chloro-3-[2-(2-methyl-1,3-thiazol-5-yl)-2-tritylaminoethoxy]-1,2-benzoisoxazole in 17 ml of chloroform and 17 ml of methanol is added 2.05 ml of a 2-propanol solution (7.5N) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for two hours, after which the solvent is removed by distillation under reduced pressure. To the residue obtained is added 2-propanol, and after stirring, the crystals precipitated are collected by filtration, to obtain 0.90 g of colorless, crystalline 5-chloro-3-[2-(2-methyl-1,3-thiazol-5-yl)-2-aminoethoxy]-1,2-benzoisoxazole hydrochloride having a melting point of 212° C.