Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>>[CH3:16][C@@H:17]1[NH:18][CH2:19][CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1

Procedure:
to The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (S)-2-methylpiperazine (0.5 g) by the method of Example 58 step (i) as a white solid. Yield: 1.4 g
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18a, 2.14 g, 10 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. LDA (1.8 M in THF, 6.6 mL) was added to the mixture dropwise and the mixture was stirred for 15 min. Then CH3I (1.87 mL, 30 mmol) was added to the mixture at −78° C. and the reaction was allowed to warm up to room temperature. The reaction was stirred overnight. NH4Cl (aq.) was added to quench the reaction which was extracted with ethyl acetate (50 mL×3). The combined organics was washed with water and brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (0-50% ethyl acetate in hexane) which gave ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b) (2.09 g) as an oil. HPLC-MS tR=1.68 min (UV254 nm); mass calculated for formula C12H20O4 228.1, observed LCMS m/z 229.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid, 20 g) in dimethylformamide was added (S)-2-amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 1.05 mol. eq.) and diisopropylethylamine (4 mol. eq.) at room temperature. The reaction mixture was cooled to 0-10° C. and stirred for 15 min. T3P (50% wt/wt in DMF; 1.7 mol. eq.) was added to the reaction mixture by dropwise addition at 0-10° C. over a period of 30 min and stirred for 1.5 h at the same temperature. The reaction mixture was quenched with water (2 rel. vol.) and stirred for 30 min at room temperature. 2-Methyltetrahydrofuran (15 rel. vol) and water (13 rel. vol) were added to the reaction mixture and extracted. The organic layer was separated and concentrated to 5 rel. vol. To the stirred organic portion was added toluene (10 rel. vol.) drop wise over a period of 30 min. The solution was stirred for 5 h at room temperature. The resulting solid material was filtered and washed with toluene (2 rel. vol), and dried the material at 50° C. under vacuum to afford the sub-titled compound (28.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH:9]O>CO>[C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: OO
Reactant: N#Cc1ccncc1
Solvent: CO
Product: N#Cc1cc[n+]([O-])cc1
Reaction time: 24 h

Procedure:
This example illustrates the use of catalytic activity of the product obtained in Example 1. A typical oxidation of substituted pyridine to substituted pyridine N-oxide was carried out as follows. 0.5 g. of the material obtained according to example 1, (x=0.064) were added to a mixture containing 10.0 g 4-Cyano pyridine and 40 ml methanol under stirring. The temperature of this reaction mixture was kept at 60° C. and then 19.8 g. of H2O2 (30%) were added drop wise to the reaction mixture under stirring. The progress of the reaction followed by Thin Layer Chromatography. Then this reaction was carried out for 24 hours. Once the reaction was complete the catalyst was removed by filtration and the solvent was distilled off under vacuum. The isolated product by this procedure contained, exclusively the corresponding N-oxide is observed from the 1HNMR and mass spectra. 4-Cyanopyridne gave 9.6 g of coresponding 4-Cyanopyridine N-oxide without any trace of byproduct.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:22])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].O>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][CH2:20][CH3:21])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:22][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)C
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCC(=O)c4ccccc4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A warm solution of 4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (266 mg, 0.891 mmol) in DMF (20 mL) was cooled to approximately 0° C. Solid cesium carbonate (580 mg, 1.78 mmol) was added. After ten minutes, 2-bromoacetophenone (186 mg, 0.935 mmol) was added in one portion, and the reaction was allowed to warm to room temperature and was stirred overnight. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material. Additional 2-bromoacetophenone was added, and the reaction was stirred for six hours. The reaction was poured into deionized water (200-300 mL) and stirred for 15 hours. The resulting precipitate was isolated by filtration and purified by column chromatography on silica gel (eluting with chloroform:methanol ranging in ratios from 99.5:0.5 to 98:2). The product was then recrystallized from acetonitrile, isolated by filtration, and dried overnight under high vacuum to provide 222 mg of 2-(4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy)-1-phenylethanone as white crystals, mp 178.0-180.0° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:33]([O:35][CH3:36])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 30 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL) is added to a suspension of sodium hydride (60% in mineral oil, 4 mg, 0.1 mmol) in dry tetrahydrofuran. After 20 min methyl chloroformate (6 μL, 0.078 mmol) is added, and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is a) extracted with dichloromethane. The combined organic layers are concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 2 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 1.10 min (V011_S01).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-:10].[K+].CN(C)C=O.Cl>[Cu](I)I.C(OCC)(=O)C>[I:10][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [I-]
Agent: I[Cu]I
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
8.0 g (43.2 mmol) of 4-bromobenzaldehyde, 107.6 g (0.65 mmol) of potassium iodide, 41.1 g (0.22 mmol) of copper iodide and 130 mL of dimethylformamide (DMF) were put in a 300 mL three-neck flask, and refluxed in a nitrogen atmosphere for 3 hours. After it was put back at a room temperature, 1N of hydrochloric acid and ethyl acetate were added, and stirred for 1 hour. It was filtered to remove potassium iodide and copper iodide, and the filtrate was washed with sodium sulfate and water, and dried with magnesium sulfate. It was distilled under a reduced pressure to obtain 4-iodobenzaldehyde (compound A). A synthesis scheme is shown below.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])[N:25]=1
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)cc1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=472.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNCCOC
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2-methoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.90-3.15 (m, 4 H), 3.27 (t, J=4.8 Hz, 4 H), 3.20-3.40 (m, 6 H), 3.77 (t, J=4.8 Hz, 4H), 6.28 (s, 1 H), 7.05 (d, J=12.4 Hz, 1 H), 7.27 (d, J=8.7 Hz, 1 H), 7.43-7.62 (m, 5 H), 7.82 (s, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.26 (d, J=5.1 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl.[CH3:16][O:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:16][O:17][N:18]=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
0.560 g (2.96 mmol) of N-(2-oxoethyl)phthalimide was dissolved in 20 ml of ethanol and to the solution was added 0.330 g (3.95 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 10 ml of 0.35M aqueous sodium carbonate solution, followed by being stirred at room temperature for 3 days. The reaction mixture was poured into 100 ml of water and extracted with chloroform (20 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with petroleum ether to give 0.291 g (yield 45%) of the titled compound as colorless crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1>C(Cl)Cl>[Cl:1][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCc1cn2ccccc2n1
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 90.4 %

Procedure:
N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (400 mg, 76%) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+: m/z=201.8. HPLC: (98.3%, Condition-A).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClC(Cl)Cl>[CH3:25][S:26]([O:13][CH:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])[CH2:8][CH2:9]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1OC1CCC(O)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCC(Oc2ccc(F)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 18.3 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol, 6.23 parts of pyridine and 135 parts of trichloromethane were added dropwise, during a 10 minutes period, 9 parts of methanesulfonyl chloride. Upon completion, stirring was continued overnight at room temperature. The whole was further stirred and refluxed for 2 hours. The reaction mixture was evaporated and the residue was stirred in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 8.5 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol methanesulfonate (ester); mp. 111.7° C. (intermediate 102).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(=S)=S>[CH3:23][O:22][C:20]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[C:12]([C:5](=[O:7])[CH3:6])[CH:13]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(O)c(C(C)=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
To a stirred suspension of AlCl3 (58 g, 440 mmol) in CS2 (500 mL) was added acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5 min, methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (15 g, 73 mmol) was added. The reaction mixture was heated at reflux for 2 h before ice water was added carefully to the mixture at room temperature. The resulting mixture was extracted with EtOAc (150 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (15 g, 81%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 12.28 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.47 (dd, J=2.0, 8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.64 (s, 3H), 2.64 (s, 3H), 1.65-1.62 (m, 2H), 1.18-1.16 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH3:12].Cl>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 5° C. 4-bromobenzylbromide (100 g, 402 mmol) in 100 mL DMF is added to a mixture of dimethylamine (40% in water, 150 mL, 1.33 mol). After 0.5 h stirring at RT, 6 M aqueous HCl is added and the reaction mixture is extracted with diethyl ether. The combined organic phases are washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue is purified by vacuum distillation (bp 58° C. at 2 mbar). Yield: 77.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([O:13][CH2:14][C:15]([O:17]C)=[O:16])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].CO.[OH-].[Na+]>O>[C:15]([CH2:14][O:13][C:6]1[C:5]([CH3:19])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])([OH:17])=[O:16]
Reactant: COC(=O)COc1c(C)cc(OC)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(OCC(=O)O)c(C(=O)O)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
The synthesis was performed with reference to the known literature (Bioorganic & Medicinal Chemistry Letters, Vol. 17, p. 6354, 2007). Methyl 5-methoxy-2-(2-methoxy-2-oxoethoxy)-3-methylbenzoate (4.9 g, 18.3 mmol) was added with methanol (30 mL), and water (10 mL), and then added with sodium hydroxide (2.2 g, 55 mmol), and the mixture was stirred at 55° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was made acidic with 3 N hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the solid formed was dried to obtain 2-(carboxymethoxy)-5-methoxy-3-methylbenzoic acid (3.9 g, 89%).
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[NH2:16][NH2:17]>CCO>[CH2:8]([O:7][C:5]([C:4]1[C:10](=[O:12])[NH:16][NH:17][C:1]=1[CH3:2])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH][nH]c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of diethyl acetylmalonate (20 g, 89.0 mmol) in EtOH (180 ml) is added hydrazine mono-hydrochloride (7.54 g, 107.0 mmol, 1.2 eq.) in one portion at RT. The reaction mixture is heated at reflux for 3 h then filtered hot. The filtrate is cooled to RT and concentrated under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH 9:1] 95:5→1:9]) to yield the title compound as a white solid. TLC: RF=0.21 (DCM/MeOH 92.5:7.5); HPLC: AtRet=0.75; MS: m/z 171.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J 7.1, 3H), 2.30 (s, 3H), 4.15 (q, J 7.1, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[C:20]([O:24][C:25]([NH:27][NH2:28])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25]([N:27]1[C:15](=[O:17])[C:3]2[CH:4]=[N:5][C:6]3[C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1[nH]c2c(cnc3c([N+](=O)[O-])cccc32)c1=O
Yield: 77.8 %

Procedure:
A mixture of 4-chloro-3-ethoxycarbonyl-8-nitroquinoline (500 mg) and tert-butoxycarbonylhydrazine (283 mg) in dioxane was refluxed for 1 hour. The mixture was concentrated in vacuo to give 2-tert-butoxycarbonyl-2,3-dihydro-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (458 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (5, 290.0 g, 698.8 mmol) in anhydrous DMF (700 mL) was treated with sodium azide (NaN3, 90.84 g, 1.4 mol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 6 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (1500 mL) and the resulting mixture was stirred at room temperature for 2 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 248.0 g, 252.97 g theoretical, 98%) as white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1023: 1H NMR. (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 31H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H8FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,5-difluoro-4-nitrotoluene (0.550 g. 3.18 mmol) in DMF (5.0 mL) was added dropwise a solution of sodium glycinate (0.308 g, 3.18 mmol, Aldrich, used as received) in water (1.0 mL). The resulting suspension was stirred at 28° C. overnight. The solid was filtered and dried under vacuum to give 0.168 g (23%) of crude product. It was purified as follows. 0.150 g material was boiled in ethyl acetate (5.0 mL) and filtered while hot to give 0.134 g (18%) of the pure (1H NMR) title compound as a yellow powder. 1H NMR (DMSO-d6): 2.213 (s, 3H), 3.428 (d, 2H, J=3.9 Hz), 6.765 (d, 1H, J=6.9 Hz), 7.700 (d, 1H, J=10.5 Hz), 8.728 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][N:5]([CH3:7])[CH:6]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:3](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc(Br)c(C=O)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc(Br)c(/C=C/C(=O)O)n1

Procedure:
A solution of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol), malonic acid (825 mg, 7.94 mmol) and piperidine (0.12 mL, 1.2 mmol) in pyridine (0.60 mL) was heated to reflux for 3 hours. The mixture was then poured into 10% HCl and extracted with ethyl acetate (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (2E)-3-(4-bromo-1-methyl-1H-pyrazol-3-yl)prop-2-enoic acid as a colorless solid.