Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]1[CH:14]=[CH:15][CH:16]=[C:11]1[C:10]2=[O:17])=[O:4].O.[OH-].[Li+]>O.CO>[O:17]=[C:10]1[C:9]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[N:12]2[CH:14]=[CH:15][CH:16]=[C:11]12
Reactant: COC(=O)c1cccc2c1-n1cccc1C2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1-n1cccc1C2=O
Yield: 83.9 %

Procedure:
In a 250 ml round-bottomed flask, a mixture of 800 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid methyl ester obtained according to the preceding stage and of 740 mg of lithium hydroxide monohydrate in 25 ml of water and 100 ml of methanol is refluxed for 3 hours. The reaction medium is evaporated to dryness under vacuum, and the solid is taken up in 35 ml of water and brought to pH 3 with 5M hydrochloric acid. A precipitate appears and the medium is extracted with 3 times 35 ml of a mixture of dichloromethane and methanol (95/5 v/v). The combined organic extracts are washed with 3 times 15 ml of water, dried over magnesium sulphate, and evaporated to dryness under vacuum. 630 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:9])[CH2:16][CH2:15]2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Clc1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (8.48 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50 mL dichloromethane were cooled with an ice/ethanol bath and combined with 1.2 g (7.81 mmol) 5-chloro-2,3-dihydro-1H-indole. 7.9 mL (7.9 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 2 h with cooling and for 1 h at RT. The man 50 mL of an aqueous saturated sodium hydrogen carbonate solution were added. After 10 min stirring the organic phase was separated off and washed with water and 1 M hydrochloric acid. The organic phases was dried on magnesium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13].[H-].[Na+].CCCCCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]#[N:10])=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:7]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C#N
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine-5-carbonitrile (1.0 mmol) and 2-(isopropylsulfonyl)aniline (1.0 mmol) in 5 mL of DMF, was added sodium hydride (24 mg). The suspension was stirred at 30° C. for 2 hours. Product was obtained after work-up and column chromatography (9:1 Hexane:EtOAc). MS (ES+): 371.01 (M+1)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]1([C:14]([C:17]2[CH:22]=[CH:21]C=[CH:19][CH:18]=2)([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1N2CN3CN(C2)CN1C3>>[CH3:16][C:14]([C:17]1[CH:22]=[CH:21][C:2]([CH:3]=[O:5])=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(c1ccccc1)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Trifluoroacetic acid (35 ml), was mixed with 3.93 g(20.0 mmol), of 2,2-diphenylpropane and 2.80 g (20.0 mmol), of hexamethylenetetramine and heated to reflux for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice water and the mixture was stirred for 1 hour. The solution was adjusted to pH=about 9 and extracted with 100 ml of diethyl ether. The organic extract was washed with saturated saline and dried with sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to obtain 3.61 g (yield: 80.5%), of the target compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)C(OC1C=CC(C2C=CC(C#N)=CC=2)=CC=1)C(O)=[O:34].[NH3:52]>O>[C:1]([O:5][C:6]([CH2:8][CH:9]([CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C:10]([NH:52][OH:34])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(CCOc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Reactant: N
Reactant: CC(C)C(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCOc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)NO

Procedure:
The desired compound was prepared according to the method of Example 29, step 5, except substituting 2-tert-butyloxycarbonylmethyl-4-[4-(4-cyanophenyl)phenoxy]butanoic acid, prepared as in step 3, for 3-methyl-2-[4-(4-cyanophenyl)phenoxy]butanoic acid. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.76-1.98 (m, 2H), 2.36 (dd, 1H, J=6, 15 Hz), 2.45-2.58 (m, 1H), 2.58-2.70 (m, 1H), 3.90-4.50 (m, 2H), 7.03 (d, 2H, J=9 Hz), 7.72 (d, 2H, J=9 Hz), 7.82-7.91 (m, 4H), 10.58 (s, 1H). MS (DCI/NH3) 411 (M+H)+, 428 (M+NH4)+, 372, 354. Anal Calcd. for C23H26N2O5.1.25 H2O: C, 63.80; H, 6.63; N, 6.46. Found: C, 63.67; H, 6.17; N, 6.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][CH3:9])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[C:6]([Cl:19])=[N:8][CH3:9]
Reactant: CNC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN=C(Cl)c1cc(OC)c(OC)c([N+](=O)[O-])c1

Procedure:
To a stirred suspension of 3,4-dimethoxy-N-methyl-5-nitro-benzamide (0.40 g, 1.66 mmol) in toluene (10 mL) was added phosphorous pentachloride (0.38 g, 1.83 mmol) portionwise. Upon completion of addition, the reaction mixture was warmed to reflux till complete disappearance of starting material. Evaporation to dryness resulted in a crude solid that was washed with diethyl ether, affording 3,4-dimethoxy-N-methyl-5-nitro-benzimidoyl chloride, 0.37 g (85%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.Br[CH2:15][C:16]([O:18]CC)=[O:17]>CN(C=O)C.O>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[N:5]1
Reactant: CCOC(=O)CBr
Reactant: Cn1ncc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2ccc(OCC(=O)O)cc21
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of NaH (146 mg, 6.06 mmol) in DMF (3 mL) was added 1-methyl-1H-indazol-6-ol (300 mg, 2.02 mmol) at 25° C. After stirring for 5 minutes, ethyl 2-bromoacetate (406 mg, 2.43 mmol) was added and stirred for 16 h at 25° C. The mixture was then diluted with water (50 mL) and washed with ethyl acetate (2×20 mL). The water layer was then acidified by adding with 2N HCL until pH3 and then extracted with ethylacetate (2×20 ml). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (300 mg, 63.4%) as colorless oil. It was used in next step without further purification. LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[ClH:7].C(=N)(OCC)[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)O.[CH2:21]([OH:23])C>>[ClH:7].[OH:23][C:21]1[N:1]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][N:6]=1
Reactant: CCO
Reactant: CCOC(=N)C(O)c1ccccc1
Reactant: NCCCCN
Agent: Cl
Product: OC1=NCCCCN1Cc1ccccc1
Reaction time: 2 h
Yield: 34 %

Procedure:
To 200 ml of absolute ethanol was added 1,4-diaminobutane at 0° C. with continuous stirring. To this solution waas added an equal molar amount of ethyl mandelimidate hydrochloride. After stirring at 0°-5° C. for two hours, the suspension was heated under reflux 12 hours then cooled and concentrated to remove any traces of NH3. The concentrated solution was acidified by dropwise addition of ethanolic HCl into the suspension which was then concentrated to dryness and the residue recrystallized several times from CH3CN/ether to yield 14.5 g (34%) of product: mp 179°-181° C. Structure was confirmed by IR and NMR.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CCC2CN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (42 mg, 0.16 mmol), NaBH3CN (40 mg, 0.66 mmol) and HOAc (40 mg, 0.66 mmol) in 20 mL DCM was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (29 mg, 0.16 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 5.28 (s, 2H), 3.50˜3.61 (m, 3H), 3.20˜3.32 (m, 4H), 2.99˜3.08 (m, 1H), 2.84˜2.95 (m, 3H), 2.67˜2.77 (m, 4H), 2.21˜2.30 (m, 1H), 1.87˜1.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=C([CH:25]=[CH:26][C:27]=1[F:28])C(O)=O)[C:13](=[O:29])[CH:12]=[CH:11]2.C(Cl)(=O)C(Cl)=O.[NH2:36][NH2:37].[CH:38]([O:45][CH2:46][CH3:47])(OCC)OCC>C(Cl)Cl.CO.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:47]([C:46]3[O:45][CH:38]=[N:36][N:37]=3)[CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: NN
Reactant: O=C(O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Reactant: CCOC(OCC)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=c1ccn2c(-c3ccc(F)cc3F)cccc2c1-c1cc(-c2nnco2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-4-fluorobenzoic acid (Example 31, 400 mg, 1.01 μmol) in CH2Cl2 (5 mL) was added oxalyl chloride (190 mg, 1.50 mmol), and a catalytic amount of DMF at 0° C. After 15 minutes at 0° C. the ice bath was removed and the reaction warmed to ambient temperature. LCMS revealed the reaction was complete and all volatile material was removed in vacuo. The crude residue was dissolved in CH2Cl2 and was added to a hydrazine solution (10.1 mmol of hydrazine in 3 mL CH2Cl2) via cannula. After stirring for 10 min, the reaction was concentrated in vacuo to yield a solid. The crude material was dissolved in MeOH (1 mL) and triethyl orthoformate (4 mL) and heated to 120° C. for 1.5 hours. LCMS revealed the reaction was complete and the mixture was concentrated in vacuo. The crude material was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to give the title compound as a yellowish solid (46 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>CN(C=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][S:7][C:8]2[C:9]([C:10]([NH:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: Fc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1cccnc1SCCCc1ccc(F)cc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (6 ml) and stirring was carried out for 1 h at RT. 325 mg (1.5 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were then added and stirring was carried out for a further 16 h at RT. The mixture was then concentrated in vacuo and the residue was taken up in an EA/water mixture. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:2), yielding 428 mg (1.1 mmol, 74%) of 2-[3-(4-fluorophenyl)-propylsulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 3871 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][Br:9])=[CH:5][CH:4]=1.C(Br)C(C1C=CC=CC=1)=O.[C:23]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1>[Br-:9].[CH2:8]([N+:30]1[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=1)[C:7]([C:6]1[CH:11]=[CH:12][CH:3]=[CH:4][CH:5]=1)=[O:10]
Reactant: CC(C)(C)c1ccncc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C(CBr)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc[n+](CC(=O)c2ccccc2)cc1
Product: [Br-]

Procedure:
Employing the procedure of Example I above but replacing 4-methoxyphenacyl bromide with a substantially equimolecular amount of phenacyl bromide and replacing pyridine with a substantially equimolecular amount of 4-tert.butylpyridine there is obtained N-(phenacyl) 4-tert.butylpyridinium bromide, a white solid melting at 247-248° C., and which is soluble in water.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Br-].[C:18]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:4]=[C:3]([C:18](=[O:25])[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:15][CH:14]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Br-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCCC(=O)O)c1
Reaction time: 2 h

Procedure:
Magnesium (0.226 g, 8.58 mmol) was flame dried in a 50 mL RB flask equipped with addition funnel and magnetic stirrer under N2. When the flask had cooled, anhydrous THF (25 mL), a pinch of iodine, and a THF solution of Rieke magnesium (1 mL) were added, followed by a small portion of 3-bromophenoxy-tert-butyl(dimethyl)silane (2.24 g, 7.80 mmol) in THF (3 mL) with slight warming to initiate the reaction. The remainder of the bromide solution (10 mL) was added dropwise over 15 min. After 0.5 h this Grignard solution was added to a solution of glutaric anhydride (0.89 g, 7.8 mmol) in THF (10 mL) with cooling in an ice-H2O bath. After 2 h, the reaction mixture was diluted with EtOAc and washed with 1N NaOH (5×) to extract the product. The aqueous basic solution was cooled in an ice-H2O bath and acidified with 12N HCl, then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification on an ISCO Combiflash eluting with 3-7% MeOH/CH2Cl2 w/NH4OH gave the title compound. MS(M+1)323.
Reaction SMILES: Br[C:2]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-].[K+].[N+:16]([C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>CN(C=O)C.O>[CH3:13][C:2]([O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
Diethyl 2-bromo-2-methylmalonate (1.0 g, 3.95 mmole) was added to a stirred suspension of potassium fluoride (0.57 g, 9.8 mmole) in dry DMF (5 mL). After stifling for 20 min at room temperature, 3-nitrophenol (0.55 g, 3.95 mmole) was added. The resulting mixture was stirred at 60° C. for 6 h, cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aq. 1N NaOH (2×75 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to provide diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). 1H NMR (CDCl3): δ 7.92 (dd, 1H, J=2.3 and 8.2 Hz), 7.82 (t, 1H, J=2.3 Hz), 7.41 (t, 1H, J=8.2 Hz), 7.30 (dd, 1H, J=2.3 and 8.2 Hz), 4.28 (qt, 4H, J=7.0 Hz), 1.81 (s, 3H), 1.26 (t, 6H, J=7.0 Hz).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[CH:11]=O.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].C(=O)=O>N1C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[CH:11]=[CH:21][C:22]([OH:24])=[O:23]
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])cc1C=CC(=O)O

Procedure:
Piperidine (1 ml) was added to a mixture of 2-methoxy-5-nitrobenzaldehyde (24 g) and malonic acid (30 g) in pyridine (about 60 ml). The mixture was warmed on a steam bath for 3 hours (slow evolution of carbon dioxide) and then poured into water (500 ml) when a yellow solid precipitated. The solid was removed by filtration and crystallized from ethanol (1 liter). The weight of the product was 20 grams.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[CH3:55][O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH2:70][NH2:71])[CH:65]=2)=[CH:60][CH:59]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:71][CH2:70][C:66]2[CH:65]=[C:64]([C:61]3[CH:62]=[CH:63][C:58]([C:57]([O:56][CH3:55])=[O:72])=[CH:59][CH:60]=3)[CH:69]=[CH:68][N:67]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccnc(CN)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccnc(CNC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (275 mg, 1.2 mmol) in CH2Cl2 (2 ml) was added diisopropylethylamine (0.23 ml, 1.32 mmol). The resulting solution was stirred for 5 minutes then TBTU (337 mg, 1.26 mmol) was added and stirred for 20 minutes. To the reaction mixture was added a solution of 4-(2-aminomethyl-pyridin-4-yl)-benzoic acid methyl ester trifluoroacetic acid salt (356 mg, 1 mmol, reference example 103a) and diisopropylethylamine (0.192 ml, 1.1 mmol) in CH2Cl2 (2 ml). The reaction mixture was stirred 45 minutes then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 40% ethyl acetate/10% methanol/hexanes) to give 455 mg of product as a white foam. MS (ion spray) m/z 454 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]([CH2:28]CO)[CH2:25][CH2:26]O)[CH3:10].S([Cl:36])(C)(=O)=O.[CH2:37]([Cl:39])Cl>>[CH3:8][N:9]([CH2:11][CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]([CH2:28][CH2:37][Cl:39])[CH2:25][CH2:26][Cl:36])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: ClCCl
Reactant: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1N(CCO)CCO
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (4.5 ml; 32 mmol) was added to a solution of 2.6 g (0.76 mmol) of N-[(N,N-dimethylamino)ethyl]-2-[N,N-bis(2-hydroxyethyl)amino]-5-nitrobenzamide in 20 ml of methylene chloride, followed by cooling over an ice bath. The thus-obtained solution was added with 1.8 ml (23 mmol) of mesyl chloride, followed by stirring at room temperature for 3 hours. After the reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, magnesium sulfate was added to the organic layer to dry the same. The solvent was distilled out under reduced pressure. The residue was dissolved in 10 ml of DMF, to which 5 g of sodium chloride were added. The resulting mixture was then stirred at 150° C. for 30 minutes. After the thus-obtained mixture was cooled to room temperature, the sodium chloride was filtered off and the solvent was distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform/methanol=10/1), whereby 0.95 g of the title compound was obtained as yellow powder (yield: 33%).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:8][O:17]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.