Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: [I-]
Reactant: O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CCI)c1ccccc1
Yield: 97.8 %

Procedure:
To a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol) in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). The resulting solution was heated at reflux for 16 h. The solution was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [100:0 to 3:1] to yield the title compound as a white solid (7.51 g, 98%); δH (300 MHz, CDCl3) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34–3.15 (2H, m, CH2), 2.28–2.15 (2H, m, CH2).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].[Br:16][C:17]1[S:18][C:19]([CH2:22]Br)=[CH:20][CH:21]=1>CN(C=O)C>[Br:16][C:17]1[S:18][C:19]([CH2:22][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Reactant: BrCc1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)s1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
NaH (60% w/w, 0.60 g, 15 mmol) was added to a solution of (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (2.00 g, 10.8 mmol) and 2-bromo-5-(bromomethyl)thiophene (prepared by the method of Mamane et al., Synthesis, 3; 2003; 455-467) (3.20 g, 12.5 mmol) in DMF (40 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then poured onto ice and extracted with EtOAc (2×200 mL). The organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc, gradient elution) gave the titled compound (2.985 g, 77%) as a white solid. APCI MS m/z 360, 362 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.11 (d, J=3.7 Hz, 1H), 6.95 (d, J=3.7 Hz, 1H), 4.79 (d, J=13.2 Hz, 1H), 4.76 (d, J=13.2 Hz, 1H), 4.60 (dt, J=12.0, 1.6 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 4.19-4.25 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:16][O:17][C:33]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(CO)Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OCC2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-[1-(4-Chloro-benzyl)-2-hydroxy-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester, the intermediate alcohol was dissolved in 15 mL of methylene chloride. Triethylamine (0.423 g, 0.00418 mol, 583 uL 1.2 equiv) was added followed by portionwise addition of carbonyl diimidazole (0.68 g, 0.00418 mol, 1.2 equiv). The mixture was stirred at room temperature and then quenched with water (15 mL). The organic layers were separated and the remaining aqueous layer was extracted with methylene chloride (3×15 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford 4-[4-(4-chloro-benzyl)-2-oxo-oxazolidin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.1 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Reaction time: 23 h
Yield: 95.6 %

Procedure:
To a stirred solution of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (7.17 g, 0.0250 mol) in tetrahydrofuran (60 mL) at room temperature was added a solution of sodium hydroxide (1.04 g, 0.026 mol) in methanol (60 mL), and the mixture was stirred for 23 hours. To the reaction was added 1.0 M aqueous sodium hydroxide (10 mL), and the mixture was stirred for an additional 24 hours. The mixture was rotary evaporated, and the residue was partitioned between water and chloroform. The aqueous layer was washed with chloroform (3×) and acidified with concentrated hydrochloric acid to pH=3. The resulting solids were filtered, washed with dilute aqueous hydrochloric acid (pH=3), and dried under house vacuum (air bleed) to give 6.51 g of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a pale yellow solid; mp 148-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH:11]=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C#CCO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cccc(C#CC=O)c1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
To a solution of 3-(3-methoxyphenyl)prop-2-yn-1-ol (500 mg, 3.08 mmol) in anhydrous DCM (20 ml) under argon was added MnO2 (7.8 g, 90 mmol) portion wise over 2 h. The reaction mixture was stirred at rt for one additional hour. Then the reaction mixture was filtered and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (cHex:EtOAc, gradient 9:1 to 4:1) gave 122 mg (25%) of the title compound as a yellow oil. HPLC, Rt: 2.9 min (purity: 99.9%). 1H NMR (CDCl3) δ: 9.43 (s, 1H), 7.32 (dd, J=8.3, 7.7 Hz, 1H), 7.22 (ddd, J=7.7, 1.4, 1.1 Hz, 1H), 7.12 (dd, J=2.6, 1.4 Hz, 1H), 7.05 (ddd, J=8.3, 2.6, 1.1 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([C:9](OC)=[O:10])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[N:5]1.[BH4-].[Li+].C(OCC)(=O)C.O>O1CCCC1>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[N:5]1
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1CCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (500 mg, 1.8 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C. and lithium borohydride (78.3 mg, 3.6 mmol) was added in portions. The resulting mixture was allowed to warm to room temperature overnight. To the resulting mixture was added ethyl acetate (20 ml) and water (50 ml). The biphasic mixture was separated and aqueous layer extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate and the resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, AnaLogix system SF25-40 g column, 20% to 60% ethyl acetate in hexanes) to give (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (158 mg, 35%) as a light yellow oil.
Reaction SMILES: COC([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:19])=O>CC#N.O>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH2:5][C:6]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1C(=O)CCN(Cc2ccccc2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CCN(Cc2ccccc2)C(=O)C1
Yield: 98.4 %

Procedure:
A solution of 1-benzyl-2,4-dioxo-piperidine-3-carboxylic acid methyl ester (2.09 g, 8.0 mmol) in MeCN (250 mL) and water (20 mL) was heated at reflux for 76 hours. The cooled reaction mixture was concentrated under vacuum to afford 1.60 g (98%) of 1-benzyl-piperidine-2,4-dione as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.36-7.24 (m, 5H), 4.69 (s, 2H), 3.48 (t, 2H), 3.43 (s, 2H), 2.54 (t, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[NH:18]([C:19]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=S)Nc1ccccc1
Temperature: 75 °C

Procedure:
To a solution of t-butyl 2-aminoethylcarbamate (1.76 ml) in ethanol (22 ml) was added dropwise phenyl isothiocyanate (1.5 g), and the mixture was heated at 75° C. for one hour. The reaction mixture was concentrated under reduced pressure and crystallized from n-hexane to give the title compound (3.25 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([OH:26])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([O:26][CH3:1])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC(=O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.90 g potassium carbonate and 1.30 ml methyl iodide are added to 4.65 g 1-tert.-butoxycarbonylamino-4-oxo-cyclohexanecarboxylic acid in 45 ml N,N-dimethylformamide and the reaction mixture is stirred for three hours at ambient temperature. Then the solvent is distilled off using the rotary evaporator and the residue is divided between 10% potassium carbonate solution and diethyl ether. The aqueous phase is separated off and extracted with diethyl ether and the combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. A colourless oil is left, which slowly crystallises.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1cc(-c2cc[nH]c(=O)n2)ccn1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn(CCCCCl)c(=O)n2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
To a solution of 4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (256 mg, 1.37 mmol) in dry DMF (45 ml), 60% NaH (71 mg, 1.78 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (305 mg, 1.78 mmol) was added and the mixture was stirred at room temperature for 1.5 hours and heated at 60° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 100 mg of the title compound that was used in the next step without further purification in the next step (27% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)CCl>[C:17]([N:24]1[CH2:25][CH2:26][N:27]([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:28][CH2:29]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-benzoic acid (4.13 g), 4-Boc-piperazine (2.97 g), EDC (3.88 g), HOBt (2.74 g), DIEA (3.33 ml) in CH2Cl2 (120 ml) was stirred at RT for 3 h. The mixture was diluted with CH2Cl2 (100 ml), washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane, CH2Cl2:hexane 1:2) to give the compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Yield: 90 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.7 mmol) in anhydrous methanol (20 ml) at to 0° C. was added thionyl chloride (3.94 g, 2.42 ml, 33.1 mmol) drop wise. The resulting solution was heated to reflux for 2 h. The cooled solution was evaporated to dryness and the residue was treated with methanol (20 ml). The resulting solution was evaporated to dryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1.97 g, 90%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-morpholinophenyl)isonicotinate (2.0 g, 5.1 mmol) was quickly dissolved in TFA (25 mL) and the light brown solution was cooled in an ice-bath. Solid sodium nitrite (0.405 g, 5.86 mmol) was added in small portions over 5 min with stirring to give a dark red mixture. After 30 min, solid sodium azide (1.24 g, 19.1 mmol) was added over 1 min followed by Et2O (25 mL). The mixture was stirred in the ice-bath for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×), brine, sat. aq. NaHCO3 solution (until aq. phases were basic), and brine (1×). After drying with sodium sulfate, the solvent was removed and silica gel chromatography (step gradient elution with hexane containing 5, 10, 15, 20% EtOAc) to afford methyl 3-azido-6-bromo-2-(4-morpholinophenyl)isonicotinate (1.27 g, 3.04 mmol, 60% yield) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.77 (2H, d, J=9.16 Hz), 7.70 (1H, s), 6.99 (2H, d, J=9.16 Hz), 4.02 (3H, s), 3.87-3.92 (4H, m), 3.26-3.31 (4H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[N:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:38][CH:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3cccnc3Oc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 535.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([O:11][CH3:12])[N:3]=1.C[C:14]([N:16](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Br:8][C:7]1[C:2]([C:14]#[N:16])=[N:3][C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(Br)c(Br)nc1OC
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(Br)c(C#N)nc1OC
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 26 %

Procedure:
To a mixture of 2,3-dibromo-5,6-dimethoxypyridine (150 mg, 0.505 mmol), Zn(CN)2 (30 mg, 0.253 mmol), Zn powder (33 mg, 0.051 mmol), Pd2(dba)3 (13.9 mg, 0.015 mmol) and DPPF (8.4 mg, 0.015 mmol), under argon, was added DMA (1.5 mL) and stirred at 120° C. for 3.5 h. Cooled to room temperature, filtered and purified by preparative HPLC (10-95% CH3CN/H2O over 20 min, 0.05% added TFA). The desired fractions were loaded onto a Strata-X-C cation exchange column. After washing the column with water and MeOH, the column was eluted with 5% NH4OH in MeOH to give 32 mg (26%) of 3-bromo-5,6-dimethoxypyridine-2-carbonitrile as a tan solid. LC/MS (M+H)+ 243.1.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:25])=[O:24]
Reactant: Cn1cc(O)c(=O)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(Cl)cc21

Procedure:
Triethylamine (3 ml) was added to a stirred mixture of 7-chloro-3-hydroxy-1-methyl-4-quinolone (2.31g), methanesulphonyl chloride (1.3 ml) and dichloromethane (70 ml) and the resultant solution stirred for 90 minutes. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (30 ml) and the solid triturated with diethyl ether (50 ml) to give the novel compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 157°-158°.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])(=[O:25])=[O:24])([O-:16])=[O:15].Cl.[CH2:47]([O:54][C:55](=[O:61])[C@@H:56]1[CH2:60][CH2:59][CH2:58][NH:57]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:47]([O:54][C:55](=[O:61])[C@@H:56]1[CH2:60][CH2:59][CH2:58][N:57]1[C:43](=[O:44])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[NH:26][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysine dicyclohexylamine (6.46 g, 10 mmole), proline benzylester hydrochloride (2.41 g, 10 mmole) and HOBT (1.35 g, 10 mmole) were dissolved in methylene chloride (30 ml), and WSC hydrochloride (1.97 g, 10 mmole) was added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C., and then overnight at room temperature, and methylene chloride (70 ml) was added to the solution. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 5% aqueous citric acid (100 ml, twice) and water (100 ml, once) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline benzylester (yield: 5.82 g, 89.2%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCCCCC>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:4])[NH:6][CH:7]=1
Reactant: Cc1ccccc1N
Reactant: Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(C(=O)Nc2ccccc2C)c1
Temperature: 80 °C
Reaction time: 75 h
Yield: 45 %

Procedure:
A solution of 2,2,2-trichloro-1-(4-methyl-1H-pyrrol-2-yl)ethanone (2 g, 8.8 mmol) in a mixture of o-toluidine (1.76 mL, 16.5 mmol) and triethylamine (2.1 mL, 15.07 mmol) under argon was heated to 80° C. with stirring during 75 h. Afterwards, the reaction mixture was concentrated to dryness giving a residue that was treated with hexane and the resulting solid filtered to afford 848 mg of the title compound (45% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(C)C.[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:29][CH:28]=1)=O>C1COCC1>[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:31][CH:32]=1)=[CH:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Lithium bis(trimethylsilyl)amide (3.46 mmol, 1M in THF) was added dropwise to a solution of methyl trimethylsilylacetate (3.46 mmol) in THF (5 mL) at −78° C. After 20 minutes at −78° C., a solution of 10.2 (2.16 mmol) in THF (9 mL) was added dropwise and the reaction was maintained at −78° C. for 1.5 hours. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 10.3. MS ESI (pos.) m/e 330.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[CH2:10][N+:11]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OCC(C(C[N+](=O)[O-])c2ccc(Cl)c(Cl)c2)O1
Agent: [Ni]
Solvent: CCO
Product: CC1(C)OCC(C(CN)c2ccc(Cl)c(Cl)c2)O1
Yield: 30.8 %

Procedure:
A solution of (4SR)-4-[(1RS)-1-(3,4-dichlorophenyl)-2-nitroethyl]-2,2-dimethyl-1,3-dioxolane (12.16 g) and Raney-nickel (10 g) in ethanol (100 ml) was stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.40 g).