Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC.[CH2:4](O)[CH3:5].COC.[C:10]1([C:12](=[CH:14][C:15](=[C:17]([CH:19]=1)[CH3:18])[CH3:16])[CH3:13])[CH3:11]>CO>[CH3:18][C:17]1[CH:19]=[CH:10][C:12]([CH3:13])=[C:14]([CH3:15])[C:4]=1[CH3:5].[C:10]1([C:12](=[CH:14][C:15](=[C:17]([CH:19]=1)[CH3:18])[CH3:16])[CH3:13])[CH3:11]
Reactant: CCO
Agent: COC
Agent: Cc1cc(C)c(C)cc1C
Solvent: CO
Product: Cc1ccc(C)c(C)c1C

Procedure:
The entire reactor system is operated at elevated pressure, 50 to 100 atmospheres, with modest pressure decreases due to pressure drop as a result of flow through the catalysts, pipes, and heat exchangers. This pressure drop is maintained at modest values to economize on the size and cost of the recycle compressor. The high pressure enhances the conversion of synthesis gas to the methanol intermediate in the first stage, has no effect in the conversion of methanol to the intermediate dimethylether. However, it is known in the art (Yurchak) that the conversion of ethanol/dimethylether to gasoline in the third stage also produces heavy gasoline, principally ≧C8 aromatics, such as tri-methyl benzenes, tetramethyl benzenes, and durene. In particular, highly undesirable tetra-methyl benzene and durene are produced which have high melting points (79° C. or greater) and limited solubility in the hydrocarbon mixture even at room temperature. Their viscometric behavior cannot be tolerated in an all-weather commercial fuel. In the present process, however, this intermediate product, containing heavy gasoline, is converted to desirable hydrocarbon products in the fourth stage by significantly reducing the trimethylbenzene and tetramethylbenzene and durene isomer groups via hydrotreating and producing desirable fuel compounds such as toluene, xylenes and C4 to C8 hydrobarbons, principally C5 to C7 hydrocarbons. This conversion is obtained by the proper choice of catalyst, space velocity and temperature of the reactor. The presence of heavy gasoline in the product produced from the third reaction is undesirable because it increases the freezing temperature of the fuel which renders the fuel unusable in cold weather. The fourth reactor converts the heavy gasoline to toluene, xylenes, and/or C4 to C8 hydrocarbon, which lowers the freezing point of the fuel product. Preferably, the fuel product coming out of the fourth reactor has a freezing point of less than about −5° C., preferably about −15 to about −20° C., while the product coming out of the third reactor has a freezing point of about 30-50° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][C:15]=12)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Yield: 87 %

Procedure:
A solution of Compound 467 (0.63 g, 1.58 mmol) and lithium hydroxide monohydrate (0.33 g, 7.90 mmol) in THF/water (10 mL, 4:1) was stirred from 0° C. to room temperature overnight. After evaporation of THF, the residue was acidified with 1N HCl to pH2 and extracted twice with 20% iPrOH/DCM. The combined organic extracts were evaporated to give Compound 471 (87% yield). LCMS (+ESI) m/z 385.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[P:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(P(c2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 3,4,5-trimethoxybromobenzene 18 (62.3 g, 0.25 mol) in dry THF (200 ml) was added BuLi solution (169 ml, 1.6M in hexane, 0.27 mol) dropwise at −78° C. within 45 min. The resulting beige-colored suspension was stirred for an additional 1 h at −78° C. Then PPh2Cl (61 g, 0.277 mol. 49.7 ml) was added dropwise. The addition was complete within 2 h. The resulting yellow solution was allowed to warm to 0° C. within 2 h and quenched by addition of NH4Cl solution (200 ml). The organic layer was separated, washed with brine (250 ml), dried (Na2SO4), filtered, and evaporated. The solid was recrystallized from methanol to give 69.5 g (80%) of 19.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.O.C(=O)([O-])O.[Na+].CN(S(F)(F)[F:21])C>ClCCl>[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][F:21])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: CN(C)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FCc1ccc(CCl)cc1
Reaction time: 24 h

Procedure:
After dissolving 4-(chloromethyl)benzyl alcohol (5.00 g) in dichloromethane (90 ml), dimethylaminosulfur trifluoride (8.28 ml) was added at room temperature and the mixture was stirred for one day. Water was added to the reaction mixture, and then a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.94 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:22][CH2:21]1)=[O:19].ClC1N=C(C2C=CC=C(C(F)(F)F)C=2)N(C)C=1C(O)=O.N1CCC(N2CCC[C@H]2COC(=O)C2C=CC=CC=2)CC1>>[Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][OH:32])[CH2:22][CH2:21]1)=[O:19]
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(Cl)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Agent: Cn1c(-c2cccc(C(F)(F)F)c2)nc(Cl)c1C(=O)O
Agent: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(Cl)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 73, benzoic acid (S)-1-{1-[5-chloro-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester [prepared in analogy to the procedure described for example 2 from 5-chloro-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carboxylic acid (example 74) and benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 6C)] has been saponified to give the title compound as colorless amorphous solid. MS: 471.2 (MH+, 1Cl).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of diethyl azodicarboxylate (7.3 g; 42 mmol) and tetrahydrofuran (15 ml) was added dropwise at 0° C. to a solution of 4-hydroxybenzonitrile (4.2 g; 35 mmol), 8-chloro-1-octanol (6.9 g; 42 mmol), triphenylphosphine (11.0 g; 42 mmol) and tetrahydrofuran (70 ml) and stirred at room temperature overnight. The reaction mixture was added to water (200 ml) and extracted with ethyl acetate (3×100 ml), dried over magnesium sulphate and filtered. The solvent was then removed in vacuo. The residue was purified by column flash chromatography on silica gel using toluene/ethyl acetate (97:3) as eluent, to give 8.8 g (94%) of p-[(8-chlorooctyl)oxy]benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
To a solution of 60 mg (0.28 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 90 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.24 ml (1.4 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.28 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 15 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:19 then 1:9) followed by a second column chromatography (8 g silica gel; gradient DCM/heptane from 70% to 90% DCM) to give 69 mg white solid (44%). MS (ISP) 549.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27]Br)[CH:20]=2)[N:12]=1.[OH-].[Na+]>O1CCCC1.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:1][C:2]1[C:3]2[CH2:9][NH:10][C:11]3[N:12]=[C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:20]=4)[CH2:25][CH2:26][CH2:27][O:8][C:5]([CH:4]=2)=[CH:6][CH:7]=1)[N:14]=[CH:15][C:16]=3[Cl:17]
Reactant: Oc1ccc(Br)c(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2nc1NCc1cc(ccc1Br)OCCCc1cccc(c1)N2
Temperature: 35 °C
Yield: 35.4 %

Procedure:
To a solution of 4-bromo-3-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]methyl}phenol (1.00 g, 1.90 mmol) in tetrahydrofuran (9.0 mL) was added a solution of sodium hydroxide in water (18 mL, 4.0 M). The resultant solution was then treated with benzyltriethylammonium chloride (30.0 mg, 0.13 mmol) and heated at 35° C. for 40 hours. The reaction mixture could not be purified by silica gel column chromatography or prep-HPLC. However, after cooling, THF and alkaline NaOH layers could be separated. THF layer was washed with brine and concentrated to give a light yellow solid residue, which was triturated with MeOH/EtOAc (90:10). After vacuum filtration, the cake was washed with MeOH to provide the desired pure product (300 mg, 35%) as an off-white powder. LCMS for C20H18BrClN4O (M+H)+: m/z=444.9, 446.9. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 7.04 (m, 2H), 6.68 (m, 1H), 6.20 (m, 1H), 4.23 (m, 2H), 4.02 (t, 2H), 3.15 (m, 1H), 2.65 (m, 2H), 1.96 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1>C(CN)O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c1C
Solvent: NCCO
Product: Cc1cccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c1C
Temperature: 190 °C
Yield: 140.1 %

Procedure:
1-(2,3-Dimethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in ethanolamine(6 ml) in the pressure tube, then refluxed at 190° C. for 3 hours. The solvent was removed by distillation under reduced pressure, then the concentrate was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 380 mg of desired compound as solid in 72% of yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]1[CH2:23][O:22][C:21]2[CH:20]=[CH:19][C:16](C#N)=[CH:15][C:14]=2[O:13]1>>[CH2:12]1[CH2:23][O:22][C:21]2[CH:20]=[CH:19][C:16]([C:1]3[NH:2][C:3](=[O:11])[C:4]4[C:5]([CH:10]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:15][C:14]=2[O:13]1
Reactant: N#Cc1ccc2c(c1)OCCO2
Reactant: CNC(=O)c1ccccc1C
Product: O=c1[nH]c(-c2ccc3c(c2)OCCO3)cc2ccccc12
Yield: 32.2 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 3,4-ethylenedioxybenzonitrile (6.41 g) were reacted, to give 3-(3,4-ethylenedioxyphenyl)isoquinolin-1-one (3.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N:19]12[CH2:26]C[CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2>C1(C)C=CC=CC=1>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:1]([O:2][C:3]([C:5]1([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4])[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C1(c2cccc(F)c2)CCCCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccc(F)c2)CCCCCC1
Temperature: 25 °C

Procedure:
1-(3-Fluoro-phenyl)-cycloheptanecarboxylic acid methyl ester (Example 12c) (0.280 g) was dissolved in toluene (100 mL) and (R)-quinuclidin-3-ol (0.320 g) was added. Toluene (10 mL) was distilled off in a Dean and Stark apparatus and after cooling sodium hydride (10 mg) was added. The reaction was refluxed in a Dean and Stark apparatus for 4 hours after which time an extra amount of sodium hydride (10 mg) was added and the reaction was heated to reflux for a further 4 hours. After allowing to cool to room temperature, the toluene was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/isohexane/triethylamine (50/50/ 1) then ethyl acetate/triethylamine (99/1) to afford the sub-titled compound (0.200 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH:16]([CH3:17])[CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]1COCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:25][CH:9]2[C:10]([N:12]2[C@@H:16]([CH3:17])[C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC1C(c2ccccc2)OC(=O)N1C(=O)/C=C/c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C[C@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
To a solution of E-3-[3-(4-Bromo-phenyl)-acryloyl]4-methyl-5-phenyl-oxazolidin-2-one from Step 5 and Pd(OAc)2 (0.05 eq.) in THF (0.2M) was added portionwise CH2N2 until the reaction was completed. NMR of aliquots monitored the reaction. The resulting mixture was concentrated and flash chromatography (Hex:EtOAc; 3:2) to afford the two separate diastereoisomers. Each diastereoisomers were submitted to the procedures described in Step 2 and Step 3 to afford the (+) and (−) enantiomers of EXAMPLE 42
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:27][C:26]3[CH:28]=[CH:29][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccc(C(F)(F)F)cc1
Yield: 72.6 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-trifluoromethylaniline (83 mg, 0.51 mmol) to give 175 mg of the title compound (73%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.38 (s, 1H), 7.77 (d, 2H, J=8.6 Hz), 7.74 (d, 2H, J=8.6 Hz), 7.24 (bs, 1H), 7.17 (bs, 1H), 5.18~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.85 (dm, 1H, J=17.1 Hz), 2.65 (d, 2H, J=7.6 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:5][N:4]1CC)[CH3:2].Cl[O-].[Na+]>>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:19])[C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C=N1

Procedure:
In accordance with the procedure of Example 12, N-(1,2-diethyl-4-pyrazolidinyl)-4-nitrobenzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:26]([O:29]CC=C)[CH:27]=[CH2:28].C(C1C=CC=C(C2C(Cl)=CC=CC=2Cl)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]2[O:15][CH:27]([CH2:26][OH:29])[CH2:28][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccccc1-c1c(Cl)cccc1Cl
Reactant: C=CCOCC=C
Agent: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: OCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Yield: 64 %

Procedure:
Treatment of 2′,6′-dichloro-1,1′-biphenyl-2-ol (17.95 g, 75.06 mmol) with potassium carbonate (41.38 g, 299.43 mmol) and allyl bromide (10.89 g, 90.08 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol (16.5 g, 59.10 mmol) with 3-chloroperoxybenzoic acid (30.59 g, 177.3 mmol, 77%) followed by potassium carbonate (20.41 g, 14.77 mmol) generally according to the procedure described for Intermediate 9 afforded 11.2 g (64%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (11.2 g, 37.94 mmol) with p-toluenesulfonyl chloride (8.68 g, 45.53 mol) generally according to the procedure described for Intermediate 10 gave 15.2 g (89%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 58.1; H, 4.05.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[O:44][C:45]2([C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=3)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)/[C:27]([O:29]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[O:44][C:45]2([C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=3)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)/[C:27]([OH:29])=[O:28])[N:25]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\OC1(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: Nc1nc(/C(=N/OC2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CCCCC2)C(=O)O)cs1
Yield: 85.3 %

Procedure:
Benzhydryl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-(4-nitrobenzyl)oxycarbonylcyclohexyloxyimino)acetate (1.3 g) was treated with aqueous formic acid as described in Example 23d to give the title compound (0.58 g, 85%) as a white solid. m.p. 184°-185° C., [Found: C: 50.94; H: 4.56; N: 12.48. C19H20N4O7S requires C: 50.89; H: 4.50; N: 12.49%] νmax (KBr) 3358, 2939, 1735, 1608, 1515, and 1346 cm-1, δH (CDCl3) 1.28 (1H, m), 1.52 (5H, m), 1.78 (2H, m), 2.01 (2H, m), 5.34 (2H, s), 6.80 (1H, s), 7.31 (2H, br s), 7.63 (2H, d), and 8.13 (2H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][C@H:43]1[CH2:47][O:46][C@@H:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@H]1C[C@@H](S)CO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl-].[NH4+].O>CCO.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCOc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(Br)cc1N
Yield: 83 %

Procedure:
5-Bromo-2-ethoxy-3-nitropyridine (805 mg, 3.26 mmol), ammonium chloride (732 mg, 13.68 mmol) and powdered iron (764 mg, 13.68 mmol) were suspended in EtOH (3.4 ml) and water (3.4 ml) and stirred for 90 min at 100° C. The reaction mixture was filtered through Celite after dilution with EtOH. The solvent was evaporated under reduced pressure, water was added and the mixture neutralised to pH=6 with sodium carbonate and extracted with dichloromethane (×3). The organic phase was washed successively with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 708 mg (83% yield, 92% purity) of the titled compound were obtained and used in the next synthetic step without further purification.