Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.Br[CH2:32][CH2:33][O:34][CH3:35]>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH2:32][CH2:33][O:34][CH3:35])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (7.5 mg, 0.19 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (50 mg, 0.13 mmol) and the mixture was allowed to stir for 10 minutes. 1-Bromo-2-methoxyethane (26 mg, 0.187 mmol) was then added and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 60 h
Yield: 84.4 %

Procedure:
Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and 1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added. The reaction mixture was stirred at 80° C. for 60 hours. The mixture was cooled down to room temperature and poured into ethyl acetate. This organic mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography with 10-20% ethyl acetate in hexanes and triturated in ethanol to afford the title compound 18 (3.49 g, 84%) as white solid. LRMS (ESI): (calc) 291.05. (found) 292.2 (MS)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:42]=[CH:41][C:12]2[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]=3[CH3:40])=[N:14][O:15][C:11]=2[CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:42]=[CH:41][C:12]2[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][C:26]([F:28])([F:27])[F:29])=[CH:22][CH:23]=4)[NH:18][C:17]=3[CH3:40])=[N:14][O:15][C:11]=2[CH:10]=1
Reactant: COc1ccc2c(-c3c(C)n(S(=O)(=O)c4ccc(C)cc4)c4cc(OC(F)(F)F)ccc34)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(-c3c(C)[nH]c4cc(OC(F)(F)F)ccc34)noc2c1

Procedure:
K2CO3 (3 eq) and 10 (2.5 g, 4.8 mmol) were heated to reflux in aqueous methanol for 2 hours at which time starting material had been consumed. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified via flash chromatography eluting with 20% EtOAc/hexanes to provide the product as a pale green solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 36 h
Yield: 33 %

Procedure:
A solution is prepared of 1 g (4.9 mM) of 2-nitro-5-bromopyridine and 917 mg (4.9 mM) of N-Boc-piperazine in 10 ml of dimethylformamide and 1.02 g (7.4 mM) of potassium carbonate are added. The reaction mixture is agitated at 120° C. for 36 hours and then cooled. 50 ml of water are then added and extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a toluene/isopropanol mixture (98/2; v/v). The product sought after is thus obtained as a yellow solid (yield=33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:22])C1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
To a solution of 100 g (0.33 mol) of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone in 1 L of DMSO, 75 g (0.42 mol) of NBS was added and the mixture was stirred over a weekend. The reaction was poured into 8 L of water and stirred for 30 min. The yellow solid formed was filtered and dried. This solid was purified by passing through a plug of 1 Kg of silica gel using hexane and 5% EtOAc-hexane to isolate the title compound. 1H NMR: (500 MHz, CDCl3): δ 7.4–8.0 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].CON(C)[C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: CON(C)C(=O)C(C)C
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Product: COC(=O)c1sc(C(=O)C(C)C)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and N-methoxy-N-methylisobutyramide were reacted by method M. The product with the molecular weight of 323.29 (C12H12F3NO4S) was obtained in this way; MS (ESI): 324 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1.[NH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>C(O)C>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][CH:17]1[NH:16][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Reactant: NC1CCc2ccccc2C1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1ccc2ccccc2c1
Yield: 53.2 %

Procedure:
A mixture of 1-(2-naphthyloxy)-2,3-epoxypropane (1.95 g), 2-aminotetralin (2.65 g) and ethanol (35 ml) is heated to the reflux temperature for 5 hours. The solvent is then evaporated off and the thus obtained solid residue is crystallized from ethyl acetate (5 ml), recovered by filtration, washed with ethyl acetate and then with ethyl ether, and dried yielding 1.8 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine, as the free base; m.p. 102°-115° C.
Reaction SMILES: [OH-].[Na+].[C:3]([NH2:7])([CH3:6])([CH3:5])[CH3:4].[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])[N:11]=1
Reactant: CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 ml 0.1N sodium hydroxide solution and 6.74 g (92.25 mmol) tert.butylamine are added to 9.23 g (50 mmol) cyanuric chloride in 200 ml toluene and stirred for 1 hour at 20° C. The pH value of the reaction is monitored continuously during this period and if necessary readjusted to pH 11-12 with 1N sodium hydroxide solution. Subsequently the solvent is removed by distillation, the residue is taken up in 150 ml water, extracted twice with 150 ml ethyl acetate each time, the organic phase is dried over magnesium sulfate and the solvent is removed. The residue is dissolved in 200 ml ethyl acetate/petroleum ether (v/v 4/1), insoluble components are removed by filtration and the filtrate is concentrated by evaporation. The crude product is purified by column chromatography (silica gel Merck 60, 5×30 cm, eluant: ethyl acetate/petroleum ether (v/v 4/1).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([C:29]2[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH:28]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: Brc1cccc(C2=CCC3(CCNCC3)CC2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Was prepared according to method A with the following variation: n-BuLi (1.6 M in hexanes (1.93 mL, 4.82 mmol)) was added drop-wise to a solution of 2,6-dibromopyridine (1.06 g, 4.48 mmol) in dichloromethane (25 mL). The reaction was stirred −78° C. for 30 min. 9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300 mg, 1.12 mmol) in dichloromethane (5 mL) was added drop-wise and the mixture was stirred at −78° C. for 1 h. White solid. Mp. 161.3-162.8° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][C:4](=[O:26])[NH:5][C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1.O>CO.Cl.[Pd]>[NH2:1][C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][C:4](=[O:26])[NH:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(C(NC(=O)C[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Yield: 80 %

Procedure:
A suspension of 52.3 g Z-Asn(Mtt)OH (100 mM) in 400 ml methanol and 100 ml IN hydrochloric acid is hydrogenated at room temperature and normal pressure in the presence of 2 g of a palladium on carbon (10%) catalyst. On completion of hydrogen uptake the catalyst is filtered off, washed with methanol and the filtrate, after addition of 13.9 ml triethylamine (100 mM) and 100 ml water, condensed in vacuo to a volume of about 300 ml. The crystalline precipitate is collected by filtration and washed with water until the washings are chloride-free. The obtained H-Asn(Mtt)OH contains 0.5-1 mole of water and decomposes above 222° C. Yield 80%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[Na+].[I-:30]>C(#N)CC>[I:30][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)nc3)c2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCC#N
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(I)nc3)c2)cc1

Procedure:
According to Scheme 33 Step 1: 1-((6-Chloropyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (2.54 mmol, 0.83 g), trimethylsilyl chloride (3.3 mmol, 0.42 mL) and NaI (7.60 mmol, 1.14 g) in propionitrile (20 mL) were heated at 140° C. for 20 minutes under microwave irradiation conditions. Then the suspension was filtered off and the solid obtained was partitioned between CH2Cl2/water. The aqueous layer was extracted several times with CH2Cl2; the organic layers were combined, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was treated with Et2O giving an 1-((6-iodopyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (600 mg, 61%) as a pale grey solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH:21]=[O:22])[C:19]=1[CH3:20])[CH2:5][N:6]([CH:14]1[CH2:16][CH2:15]1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:23][C:24]1[CH:25]=[C:26]([Mg]Br)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[C:9]([O:8][C:7](=[O:13])[N:6]([CH2:5][C:4]1[CH:17]=[C:18]([CH:21]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[OH:22])[C:19]([CH3:20])=[C:2]([Br:1])[CH:3]=1)[CH:14]1[CH2:15][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C=O
Solvent: C1CCOC1
Product: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(O)c1cccc(F)c1
Temperature: 25 °C

Procedure:
To a THF (0.13 M) solution of tert-butyl (3-bromo-5-formyl-4-methylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step was added at 0° C. 3-fluorophenyl magnesium bromide (0.5 M in THF, 1.1 eq.). The resulting solution was warmed slowly to RT over 2 h before it was quenched with sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)cc1C#N
Temperature: 84 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)benzonitrile (Intermediate Example 4) (2.02 g, 5.57 mmol) and 3-{[2-(dimethylamino)ethyl]-oxy}aniline dihydrochloride (1.67 g, 6.58 mmol) in trifluoroethanol (20 mL) was added HCl (0.700 mL, 4M in dioxane, 2.8 mmol). The reaction was stirred at 84° C. for 2 days. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4), concentrated and triturated with diethyl ether to provide the title compound (2.63 g, 5.18 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 6H), 2.57 (t, J=5.7 Hz, 2H), 3.96 (s, 5H), 6.55 (d, J=8.4 Hz, 1H), 6.63 (d, J=5.1 Hz, 1H), 7.07 (t, J=7.0 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.74 (d, J=9.2 Hz, 1H), 7.92 (dd, J=9.0, 2.0 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 8.39 (d, J=5.1 Hz, 1H), 9.49 (d, J=6.2 Hz, 1H), 9.77 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:7])=[O:6])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:26]1CC[CH2:28][CH2:27]1>>[CH3:28][C:27]([CH2:1][C:2]([CH2:4][C:5]([OH:7])=[O:6])=[O:3])=[O:26]
Reactant: C1CCOC1
Reactant: CC(=O)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(=O)CC(=O)CC(=O)O
Yield: 85.2 %

Procedure:
A solution of the diacetate from stage (c) (7 g) in tetrahydrofuran (150 ml) was treated with tetra-n-butylammonium fluoride (1.4 g) at room temperature for 18 h. Tlc (ether/light petroleum, 6:1) showed one major product with traces of slow moving products due to partial deacetylation. The mixture was concentrated, taken up in dry pyridine (50 ml) and treated acetic anhydride (7 ml) at room temperature for 3 h. Tlc ether/light petroleum (7:1) showed only one product. The reaction mixture was concentrated and was eluted from short column of silica gel (50 g) with ether/light petroleum (1:1) to give a crystalline product (4.3 g, 85.2%) identical with the product from Route 1, m.p. 133°-134° [α]D20 +116.3° (c 1.0, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:20])([CH3:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:27])[C:14]([CH3:20])([CH3:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: [BH3-]C#N
Reactant: COc1cc(N2CCC(=O)C(C)(C)C2)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCC(N)C(C)(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of 1-(3-Methoxy-4-nitrophenyl)-3,3-dimethylpiperidin-4-one (INTERMEDIATE 39) (278 mg, 1 mmol) and ammonium acetate (771 mg, 10.0 mmol) in MeOH (5 mL) was stirred at RT overnight. Sodium cyanoborohydride (75 mg, 1.2 mmol) were added. The reaction was stirred at RT for 2 h. MeOH (20 mL) and silica gel (5 g) was added. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (5% MeOH and 1% NH4OH in CH2Cl2) to give the title product (0.2 g, 72.0%).
Reaction SMILES: [Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([Cl:19])[CH:3]=1.C(N(C(C)C)C(C)C)C.[I-].ClC1C=CC=C[N+]=1C.[NH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1>ClCCl>[Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[C:8]([C:9]([N:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)=[O:11])=[CH:12][CH:13]=[CH:14][N:15]=2)=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)c(Br)cc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 2-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.14 mmol, 1.0 equiv; Example 163, Step 1) in anhydrous dichloromethane (1.5 mL) was added N-ethyldiisopropylamine (152 mg, 200 μL, 1.18 mmol, 8.4 equiv; [CAS RN 7087-68-5]) and 2-chloro-1-methylpyridinium iodide (42 mg, 0.17 mmol, 1.2 equiv; [CAS RN 14338-32-0]) and the reaction mixture stirred at rt. After 1 h, 1,2,3,4-tetrahydro-quinoline (22 mg, 21 μL, 0.17 mmol, 1.2 equiv; [CAS RN 635-46-1]) was added and stirring at rt continued over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 41 mg (61%) of the title compound as a white powder. MS (ISP): 476.9 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:12][C:11]1[C:13]([O:14][CH3:15])=[CH:16][C:6]([CH:5]=[O:17])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
1,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:28]=1[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:28]=1[CH2:29][C:30]1([NH:33][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=2)[OH:25])[CH2:32][CH2:31]1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: Cc1cccc(C)c1CC1(N)CC1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1CC1(NCC(O)c2ccc(O)c(CO)c2)CC1

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 64 mg (14%, trifluoroacetate); mass spectroscopy: [M+H]+=342.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:4].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH2:3]([O:5][C:6]([C:7]1([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:4]
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (55% in mineral oil, 0.72 g) was added to a solution of (4-bromo-pyridin-2-yl)-acetic acid ethyl ester (1.80 g) in N,N-dimethylformamide (20 mL) chilled in an ice bath. The resulting mixture was stirred for 10 min at room temperature and then cooled again in an ice bath. 1,2-Dibromoethane (0.70 mL) was added dropwise and the cooling bath was removed. The mixture was stirred at room temperature overnight. Brine was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 95:5→1:1) to give the title compound as an oil. Yield: 1.28 g (64% of theory); Mass spectrum (ESI+): m/z=270/272 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.C(O)(=O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[NH2:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a suspension of 6-chloro-3-nitro-pyridine-2-carbonitrile (5.5 g, 30 mmol) in water (100 ml), was added acetic acid (5.4 ml, 90 mmol). The mixture was stirred at room temperature for 20 minutes. Then, Na2S2O4 (20 g, 86%, 90 mmol) was added slowly. The reaction mixture was stirred at room temperature for another 2 hours. The precipitate was filtered off and washed with cold water (2×10 ml). The precipitate was dried over P2O5 yielding the title compound as a yellowish solid (3.7 g, yield: 80%) which was characterised as follows: