Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[CH2:10]1)[CH3:8].[CH3:19][S-:20].O>CN(C=O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:18])[CH3:1])[C:6]1([CH:9]1[CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][S:20][CH3:19])[OH:16])[CH3:8]
Reactant: CC(C)=CC[C@H]1O[C@]1(C)[C@H]1C[C@H](O)CC[C@]12CO2
Reactant: C[S-]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC1(O)CCC(O)CC1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 5-demethoxyfumagillol (280 mg) in N,N'-dimethylformamide (2 ml), thiomethoxide (220 mg) was added, and the mixture was stirred at room temperature for 1 hour. After adding water (20 ml) thereto, the reaction mixture was extracted with isopropyl ether (50 ml). The organic layer was washed with saturated sodium hydrogen carbonate solution (10 ml) and brine (20 ml), dried over anhydrous magnesium sulfate, and filtered. The residue after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 180 mg of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6](C=O)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[CH:20]=[CH:19]4)[N:10]=2)[N:3]=1.Cl.[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30]C)C.[BH-](OC(C)=O)(OC(C)=O)[O:35]C(C)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:6]([CH2:30][N:29]2[CH2:27][CH:33]([OH:35])[CH2:32]2)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[CH:20]=[CH:19]4)[N:10]=2)[N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCN(CC)CC
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1CN1CC(O)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a slurry of intermediate 8 (77 mg, 0.23 mmol), 3-azetidinole hydrochloride (50 mg, 2 equiv.) and triethylamine (30 mL, 1 equiv.) in 20 mL of dichloromethane, was added NaBH(OAc)3 (146 mg, 3 equiv.) at room temperature. The reaction was stirred for 15 hour at room temperature and then quenched with 1N—NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by recrystallization in a mixture of ethyl acetate and heptanes to afford desired Compound No. 140 as a pale yellow solid (62 mg, 69%); MS (ESI) m/z 390 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C=O.O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24].[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1cc2[nH]cnc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cnc3ccncc32)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28 %
Yield: 8 %

Procedure:
In 3 mL of dimethylformamide, 119 mg (1.00 mmol) of imidazo[4,5-c]pyridine was dissolved, and 138 mg (1.00 mmol) of potassium carbonate and 141 mg (1.00 mmol) of 4-fluoronitrobenzene were added thereto and the mixture solution was stirred at 80° C. for two hours. The solution was diluted with 10 mL of water, and the formed precipitate was collected by filtration, washed with water, and vacuum dried. The obtained crude product was separated by a silica gel column (Si-10, a product of Kusano Co., Ltd., column 30 cm, dichloromethane:methanol=15:1) to obtain 18.9 mg (8%) of 3-(4-nitrophenyl)-3H-imidazo[4,5-c]pyridine and 66.6 mg (28%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine as yellow solids, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](Cl)=[O:10].[CH3:13][NH2:14].O.Cl>C1COCC1.CO>[CH3:13][NH:14][C:9](=[O:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CN
Reactant: Cc1ccccc1C(=O)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
The crude 2-(2-methylphenyl)glyoxyloyl chloride (0.91 g, 5 mmol) were dissolved in dry THF (10 ml), and a 40% solution (1.55 g) of methylamine (20 mmol) in methanol was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added to the reaction mixture which was then adjusted to below pH 2 by addition of conc. HCl and extracted with ethyl acetate (100 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-oxoacetamide (0.45 g; yield, 50.8%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14]3[NH:31][C:17]4=[N:18][C:19]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28](O)=[O:29])[CH2:23]5)=[CH:20][CH:21]=[C:16]4[N:15]=3)[CH2:13][CH2:12]2)[CH:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1([C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:22]([C:19]3[N:18]=[C:17]4[NH:31][C:14]([C:11]5([N:9]6[CH:10]=[C:6]([Cl:5])[CH:7]=[N:8]6)[CH2:12][CH2:13]5)=[N:15][C:16]4=[CH:21][CH:20]=3)[CH2:23]2)=[O:29])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
Azetidine (0.1 mL, 1.42 mmol) was added to a solution of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (50 mg, 1.29 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 1.29 mmol) and diisopropylethylamine (0.1 mL, 3.88 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 h, then was partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (35 mg). MS (ES+APCI) (M+H) 426.1; LCMS retention time: 3.440 min (Method S1).
Reaction SMILES: [CH2:1]([CH:3]([CH2:32][CH3:33])[CH:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:32]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:20][CH:21]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:33]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl]amino}propanoate (330 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (272 mg, 91%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]([C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:20]#[N:21])=[O:16])=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH:5]=[C:4]([Cl:31])[N:3]=1.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]([C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:20]#[N:21])=[O:16])=[C:13]([CH:26]([CH3:27])[CH3:28])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH:5]=[C:4]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[N:3]=1.[Cl:31][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[N:7]=[C:6]([CH2:8][N:9]2[C:14]([C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:20]#[N:21])=[O:16])=[C:13]([CH:26]([CH3:27])[CH3:28])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)nc(Cl)n2)c1
Solvent: CC#N
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)nc(Cl)n2)cc1
Product: COc1ccc(CNc2nc(Cl)cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)n2)cc1
Temperature: 25 °C
Yield: 25 %
Yield: 54 %

Procedure:
A mixture of 3-[3-(2,6-Dichloro-pyrimidin-4-ylmethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (458 mg, 1 mmol) and p-methoxy benzylamine (262 μl, 2 mmol) in acetonitrile (10 ml) was refluxed for 2.5 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (1:2)) to afford 143 mg (25%) of 3-{3-[2-Chloro-6-(4-methoxy-benzylamino)-pyrimidin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl}-5-methyl-benzonitrile (Rf=0.14) and 302 mg (54%) of 3-{3-[6-Chloro-2-(4-methoxy-benzylamino)-pyrimidin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl}-5-methyl-benzonitrile (Rf=0.06) as a white solid, respectively.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([C:22](=O)[CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[OH:26])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O>C1(C)C=CC=CC=1>[CH:28]1[C:27]([CH:25]([OH:26])[CH2:24][CH2:23][CH2:22][N:20]2[CH2:21][C:5]3[C:4]4[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=4[N:7]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[C:6]=3[CH2:18][CH2:19]2)=[CH:32][CH:31]=[C:30]([F:33])[CH:29]=1
Reactant: O=C(CCC(O)c1ccc(F)cc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1.16 g 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyryl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.0025 mole) in toluene (35 ml) was stirred under nitrogen while 0.0132 mole of sodium bis(2-methoxyethoxy)aluminum hydride (70% in benzene) was added. The resulting mixture was heated on a steam bath one hour, cooled to room temperature and poured into water, and extracted with ethyl acetate. The organic layer was concentrated in vacuo. The resulting residue was chromatographed on silica gel with ethyl acetate as eluant and monitoring by tlc (two solvent systems: 9:1 CHCl3 :methanol and acetonitrile) with authentic flutroline as control. Product fractions were combined, evaporated to drynes, the residue triturated with diisopropyl ether to yield title product, 175 mg; m.p. 141.5-144; mixed up with authentic flutroline, no depression.
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])([CH3:17])[CH2:3][C:4]([C:13]([F:16])([F:15])[F:14])([O:8][Si](C)(C)C)[CH2:5][C:6]#[CH:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:8][C:4]([C:13]([F:14])([F:15])[F:16])([CH2:5][C:6]#[CH:7])[CH2:3][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])([CH3:1])[CH3:17]
Reactant: C#CCC(CC(C)(C)c1ccccc1C(N)=O)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCC(O)(CC(C)(C)c1ccccc1C(N)=O)C(F)(F)F
Reaction time: 1 h
Yield: 93.5 %

Procedure:
2-(1,1-dimethyl-3-trifluoromethyl-3-trimethylsilanyloxyhex-5-ynyl)benzamide (108 mg, 0.28 mmol) was treated with a 1M solution of TBAF in 3 mL of THF. The reaction mixture was stirred for 1 hour then diluted with 50 mL of ethyl acetate, washed with 25 mL of 1 M aqueous HCl, two 25 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography (12 g SiO2, hexanes to 1:1 hexanes:EtOAc) to give 2-(3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzamide as a white solid (82 mg, 93%). MS (ES+) m/z 314 [M+H]+.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[OH2:16]>CO>[CH3:7][S:8]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)(=[O:1])=[O:16]
Reactant: CSc1ccc(O)cc1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
Oxone (65.8 g, 0.108 mol) in water (290 ml) was added to a cooled (ice-bath) solution of 4-(methylmercapto)phenol (5 g, 36 mmol) in methanol (290 ml). The resulting solution was stirred at ambient temperature for 48 h. and then concentrated in vacuo. The residue was diluted with water (100 ml) and extracted with dichloromethane (10×100 ml). The combined organic layers were dried over sodium sulphate and removal of the solvent in vacuo gave the title compound as a clear oil (5.66 g, 92%). 1H NMR (250 MHz, CDCl3) δ7.80-7.75 (2H, d, J 11.7 Hz), 7.28 (1H, br s), 7.01-6.96 (2H, d, J 11.7 Hz), and 3.08 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:37])[CH2:28][N:27](CC3C=CC=CC=3)[CH2:26]2)=[O:24])=[CH:18][CH:17]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[O:37])[CH2:26][NH:27][CH2:28]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CNC4)cc3)c2cc1OC
Reaction time: 16 h
Yield: 31.8 %

Procedure:
To a solution of ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10% mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjected to hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for 16 hr. The reaction mixture was filtered through celite and washed with MeOH. After removal of solvent in vacuo, the crude product was purified using preparative HPLC (solvent system: MeCN/H2O/NH4OAc), affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) azetidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid. 1HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).
Reaction SMILES: [CH:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[CH3:14][C:15]1[CH:16]=C[C:18](S(O)(=O)=O)=[CH:19][CH:20]=1.C([OH:28])(C)C>[Cl-].[Na+].O>[CH:11]([O:10][CH:1]([O:6][CH:7]([CH3:8])[CH3:9])[C:15]([CH3:16])([CH3:14])[C:20](=[O:28])[CH2:19][CH3:18])([CH3:12])[CH3:13]
Reactant: CC(C)O
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reaction time: 3 h

Procedure:
To a solution of keto aldehyde 19 (6.40 g, 50 mmol) in isopropanol (100 mL) was added triisopropyl orthoformate (16.7 mL, 75 mmol) and p-TsOH (951 mg, 5.0 mmol). After the mixture was stirred for 3 h, it was poured into brine (100 mL) and extracted with ether (3×100 mL). The combined organic layers were dried and concentrated in vacuo to give 50 as a pale yellow liquid (10.12 g, 88%: IR (neat) 2976, 2935, 1697, 1460, 1379, 1314, 1174, 1125, 1082, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.58 (s, 1H), 3.80 (sept, J=6.1 Hz, 2H), 2.51 (q, J=7.2 Hz, 2H), 1.18 (d, J=6.2 Hz, 6H), 1.12 (s, 6H), 1.08 (d, J=6.2 Hz, 6H), 0.95 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 215.8, 104.0, 70.7, 53.4, 32.8, 23.8, 22.4, 20.3, 8.0; HRMS calcd for C10H19O2 (M-C3H7) 171.1385, found 171.1377.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:6][CH:5]=1
Reactant: CC(C)(O)CNc1cc(Cl)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 103a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2-hydroxy-2-methyl-propylamino)-5-nitro-benzoic acid amide (300 mg, 0.67 mmol), morpholine (233 μL, 2.7 mmol), DIPEA (1.1 mL, 6.7 mmol) and MeCN (3 mL) in a microwave oven at 150° C. (45 min). Yield: 324 mg. HPLC Rt=1.58 min (method H). MS m/z: 499 [M+H]+.
Reaction SMILES: O=C[C:3]([O:5][CH2:6][CH3:7])=O.COC1C=C(N)C(N)=CC=1.CO[C:20]1[CH:21]=[C:22]2[C:27](=CC=1)[NH:26][C:25](=[O:30])[CH:24]=[N:23]2>C1(C)C=CC=CC=1.C(O)C>[CH3:3][O:5][C:6]1[CH:7]=[C:27]2[C:22]([N:23]=[CH:24][C:25](=[O:30])[NH:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C=O
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Agent: COc1ccc(N)c(N)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc2ncc(=O)[nH]c2c1
Yield: 42 %

Procedure:
A 50% solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene was added to a solution of 4-methoxybenzene-1,2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was refluxed for 2 h. The reaction was concentrated in vacuo and crystallized from ethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50 mmol, 42% yield). MS (LC/MS) R.T.=0.68; [M+H]+=177.10.
Reaction SMILES: S(=O)(=O)(O)O.NC1C(=O)N2C(C([O-])=O)=C(C[N+]3(C)CCCC3)CS[C@H]12.Cl.[NH2:27][CH:28]1[C:53](=[O:54])[N:30]2[C:31]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]12.[CH:55](=O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH:55](=[N:27][CH:28]1[C:53](=[O:54])[N:30]2[C:31]([C:37]([O:39][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]12)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=Cc1ccccc1
Agent: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)CCCC1
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12

Procedure:
Temperature stable crystalline mono-hydrochloric and sulfuric acid addition salts of 7-amino-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate substantially free of Δ2 isomer are intermediates for the preparation of broad spectrum 7-[α-(2-aminothiazol-4-yl)-α-(Z)-methoxyiminoacetamido]-3-[(1-methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylates. The monohydrochloric acid addition salt intermediate is prepared by a process comprising the steps of (1) neutralizing diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride, (2) reacting the resulting free base with benzaldehyde to produce diphenylmethyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate, (3) reacting the resulting product with sodium iodide to convert the chloromethyl group to iodomethyl, (4) reacting the resulting product with N-methylpyrrolidine to give the quaternized product diphenylmethyl 7-benzylideneamino-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate iodide, and (5) reacting with hydrochloric acid to form said intermediate.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28]C(=O)OC(C)(C)C)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36]>C(OCC)(=O)C.CO>[ClH:36].[ClH:36].[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH2:28])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 90 %

Procedure:
A mixture of tert-butyl (1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexylcarbamate (2.71 g, 5.7 mmol), a 4N hydrogen chloride in ethyl acetate solution (10 ml) and methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (2.29 g, 90%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.O1CCCC1.C(O)C.[N:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]=[S:33]>C(OCC)(=O)C>[Cl:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:7][C:2]=1[NH:1][C:32]([NH:31][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[S:33]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)CN=C=S
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=S)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.0 g, 8.89 mmol) in a tetrahydrofuran/ethanol solution (1:1) is treated with ethyl isothiocyanatoacetate (1.93 g, 13.34 mmol), refluxed for 9 hours, stirred at room temperature overnight, and concentrated in vacuo to obtain an orange-brown gum. Flash column chromatography of the gum using silica gel and 25% to 30% ethyl acetate in hexanes solutions gives the title product as a white foam (2.24 g, 52% yield, mp 95-103° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.