Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:21])[CH2:18][CH2:19][CH2:20][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (1.50 M, in hexane) (0.5 ml) was added dropwise to a solution of 1,4-diiodobenzene (250 mg) in anhydrous THF (3 ml) at −78° C., and the resulting mixture was stirred at −78° C. for 30 minutes. Oxepan-4-one (151 mg) was added to the reaction solution, and the resulting mixture was stirred at −78° C. for 1 hour. Saturated aqueous ammonium chloride solution was added thereto, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=5/1) to obtain 4-(4-iodophenyl)oxepan-4-ol (89 mg). (2) Under an argon atmosphere, a solution of 4-(4-iodophenyl)oxepan-4-ol (86 mg) obtained in (1) in anhydrous DMF (1.0 mL) was added to a suspension of sodium hydride (60 wt %) (16 mg) in anhydrous DMF (1.0 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.025 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 10 hours. Saturated brine was added thereto, and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1) to obtain 4-(4-iodophenyl)-4-methoxyoxepane (63 mg).
Reaction SMILES: [C@H:1]1([C:10]([OH:12])=O)[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(O[CH2:16][CH2:17][CH2:18][CH3:19])=O.[CH3:20]CCCCCCC.S(Cl)(Cl)=O.C[Zn]C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([C@@H:1]1[CH2:2][CH2:3][C@H:4]([C:7]([O:9][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])[CH2:5][CH2:6]1)(=[O:12])[CH3:20]
Reactant: CCCCOC=O
Reactant: CCCCCCCC
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Zn]C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(C)=O)CC1
Temperature: 110 °C

Procedure:
To a flask were added cis-cyclohexane-1,4-dicarboxylic acid (20 g, 116 mmol), n-butyl formate (581 ml, 5066 mmol), Dowex 50W×2 resin (87 grams), and octane (484 ml). The reaction mixture was heated to 110° C. overnight and then cooled and filtered. The resin was washed with 300 mL 1:1 hexane:EtOAc. The filtrate was concentrated and then taken up in toluene and re-concentrated. The resulting residue was dissolved in dichloromethane (119 ml) and then thionyl chloride (11.51 ml, 158 mmol) was added. The reaction mixture was heated to 38° C. overnight and then concentrated. The residue was taken up in DCM and re-concentrated (3×) to remove residual HCl. The resulting residue was dissolved in 1,4-dioxane (413 ml) and degassed with Ar for 30 minutes. Palladium (II) acetate (0.696 g, 3.10 mmol) was added and the mixture was degassed for an additional 30 minutes. Dimethyl zinc (2 M in toluene, 31.0 ml, 62.0 mmol) was added. The system was placed under argon through 3 cycles of evacuation and argon flushing then reacted at 38° C. overnight. The reaction mixture was cooled and diluted with water. The resulting mixture was filtered through a CELITE plug and then the solid was washed with EtOAc. The filtrate was concentrated and purified by column chromatography on silica gel (0-30% ethyl acetate/hexanes) to afford butyl cis-4-acetylcyclohexanecarboxylate. 1H NMR (500 MHz, DMSO-d6) δ 4.07 (t, J=6.6 Hz, 2H), 2.54-2.48 (m, 1H), 2.44-2.38 (m, 1H), 2.13 (s, 3H), 2.01-1.93 (m, 2H), 1.81-1.57 (m, 9H), 1.41-1.32 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1[C:11]2C=CC3C=CC=CC=3[CH:6]([C:16]([NH:27][C:28](=O)C)(C(OCC)=O)C(OCC)=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:31].[Na+].Cl.[CH3:34][OH:35]>O>[CH:11]1[C:5]2[CH:4]=[CH:6][C:5]3[CH:11]=[CH:1][CH:2]=[CH:3][C:4]=3[CH:16]([NH:27][CH2:28][C:34]([OH:35])=[O:31])[C:6]=2[CH:3]=[CH:2][CH:1]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C1c2ccccc2C=Cc2ccccc21
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CNC1c2ccccc2C=Cc2ccccc21
Temperature: 100 °C

Procedure:
A mixture of diethyl 2-(5H-dibenzo[a,d]cyclohepten-5-yl)-2-acetamidomalonate (20.2g, Example 1b) and sodium hydroxide (4g) in methanol (75ml) and water (75ml) was heated to reflux for 8h. To the cooled solution was added 1M-HCl until pH=6. The solution was concentrated in vacuo and acidified to pH=2 by addition of 1M-HCl. The solid which formed was collected by filtration and heated together with 6M-HCl for 3h at 100° C. The cooled solution was filtered and the residue dissolved in hot water, refiltered and to the filtrate was added aqueous ammonia until pH 7-8. The solid which formed on cooling to room temperature was collected by filtration and dried in vacuo to give 5H-dibenzo[a,d]cyclohepten-5-ylglycine. 1H NMR (360MHz, d4MeOH), δ 4.08-4.12 (1H, m), 4.35-4.39 (1H, m), 7.0-7.11 (2H, m), 7.24-7.30 (3H, m), 7.34-7.45 (5H, m).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C)C=O>[C:1]([CH2:2][CH2:3][C:4]([Cl:13])=[O:5])([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of mono-methyl succinate, (150 g, 1.135 mol) in 900 ml of methylene chloride and 3 ml of N,N-dimethylformamide was added 119 ml (1.26 mol) of oxalyl chloride, while keeping the pot temperature below 5° C. After the addition was complete, the reaction mixture was stirred at 0° C. for 1 hour and then concentrated to vacuo to give a crude yellow liquid, which was used without purification in the Rosenmund reduction.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][CH:16]([CH2:19]O)[CH2:17]O>>[CH3:15][CH:16]1[CH2:19][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:17]1
Reactant: CC(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CC1COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-methyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of170° to 171° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])=[O:4].[O-:45][C:46]#[N:47].[K+].C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[O:45]=[C:46]1[NH:47][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33]
Reactant: N#C[O-]
Reactant: O=C(CCl)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CNC(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 81.2 %

Procedure:
A solution of (2S,4S)-2-(chloroacetylamino)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.0 g), potassium cyanate (1.3 g) and tetra-n-butylammonium iodide (0.2 g) in acetonitrile (50 ml) was stirred at 60°-80° C. for 8 hours To a reaction mixture was added ethyl acetate (150 ml) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (50 g) eluting with a mixture of chloroform and acetone (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.82 g).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:4]=2[O:5]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)OCO2
Yield: 57 %

Procedure:
The mixture of sesamol (13.8 g, 100 mmol, methyl bromoacetate (15.3 g, 100 mmol) and potassium carbonate in acetone (200 ml) was refluxed for 24 h with stirring. Acetone was removed under reduced pressure. The residue was dissolved in water (200 ml) and was extracted with ether (2×100 ml). The combined organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give methyl 2-[3,4-(methylenedioxy)phenoxy]acetate as an oil (12 g, 57% yield). The aqueous phase was neutralized to pH 2-3 with concentrated HCl and the precipitated solid was filtered to get 2-(3,4-(methylenedioxy)phenoxy]acetic acid as a solid (6 g, 31% yield).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:19]([NH:22][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCNCC1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (5.0 g, 18 mmol) and propan-1-amine (20.0 g, 339 mmol) in toluene (50 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude tert-butyl 2-((propylamino)methyl)pyrrolidine-1-carboxylate that was used directly without further purification. LCMS ESI (+) m/z 243 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([S:24]([CH3:23])(=[O:26])=[O:25])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CNCC1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC1CCCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g) in methanol (30 mL) was added a solution of methylamine (0.83 g) in methanol (3 mL). The reaction mixture was stirred for 72 hours and then sodium borohydride (0.76 g) and molecular sieves were added. After stirring for 2 hours, the reaction mixture was filtered and the filtrate reduced in vacuo. The residue was re-dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried (MgSO4) and reduced in vacuo to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g). To a solution of 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 mL) was added triethylamine (0.36 mL) followed by methanesulfonyl chloride (0.20 mL). After stirring for 3 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (0.63 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide hydrochloride (0.49 g).
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of ethyl 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (20 mg, 0.04 mmol, prepared according to example 3) in MeOH (3 mL), H2O (1 mL) was added NaOH (4.7 mg, 0.12 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (10 mL), acidified with 1N HCl to pH=3-4 and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (20 mg, 100% yield) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:24][CH2:25][CH3:26])[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:12].[BH4-].[Na+]>C(Cl)Cl.C(O)C.O>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH:14]([O:13][CH2:11][CH3:12])[O:24][CH2:25][CH3:26])=[CH:4][CH:5]=1)=[CH2:8]
Reactant: CCOC(CNCCCCCCN)OCC
Reactant: C=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(CNCCCCCCNCC(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Formylstyrene, 1c (2.98 g, 22.5 mmol) and 2c (5.00 g, 21.5 mmol) were weighed into a 250 mL 3-neck RB flask and ethanol (90 mL) added forming a colourless solution. The flask was then attached to two B19 stoppers (side-arms) and a B24 double-layer coil condenser (centre-socket) and this in turn connected to a nitrogen-vacuum manifold. The apparatus was flushed with nitrogen and the reaction mixture stirred overnight at room temperature. Next day 3-(diethylenetriamino)propyl-functionalised silica gel (1.85 g, 1.23 mmol/g loading) was added to the reaction mixture which was stirred at room temperature under nitrogen for a period of 6 hours in order to scavenge the excess 4-formylstyrene. Sodium borohydride (1.22 g, 32.2 mmol) was then added to the reaction mixture which was then stirred at room temperature for a period of 65 hours under nitrogen. Water (100 mL) was then added to the reaction mixture via syringe in order to quench the reaction. The reaction mixture was then stirred for 30 minutes at room temperature before the ethanol was stripped from the mixture in vacuo using a rotary evaporator to yield a white emulsion. CH2Cl2 (100 mL) was added to this residue and the resultant mixture transferred to a 250 mL-separating funnel. Water (10 mL) was added to the funnel which was then shaken and the layers partitioned and the lower organic layer decanted off. The aqueous layer was discarded and the organic layer then extracted with a further 2×100 mL portions of brine. The layers were partitioned and the lower organic layer collected and dried over anhydrous MgSO4 for a period of 1 hour. The drying mixture was filtered and the collected solid washed with 3×20 mL portions of CH2Cl2. The filtrate and washings were combined and stripped to dryness in vacuo using a rotary evaporator for a period of 1 hour to yield a very pale yellow oil. This was then further dried in vacuo (0.25 torr) at room temperature for a period of 20 hours. Yield: 6.82 g (91%, pale yellow oil). NMR (CDCl3) δ 1.21 (t, 6H, —CH3), 1.32 (bm, 4H, —CH2—), 1.48 (bm, 4H, —CH2—), 2.61 (triplet of doublets, 4H, hexamethylene bridge >NCH2—), 2.71 (d, 2H, 2,2-diethoxyethyl NCH2—), 3.54 (m, 2H, HA of OC(HA)(HB)—), 3.69 (m, 2H, HB of OC(HA)(HB)—), 3.76 (s, 2H, >NCH2Ar), 4.59 (t, 1H, —CH(OR)2), 5.20 (d, 1H, ═C—H), 5.72 (d, 1H, ═C—H), 6.70 (dd, 1H, ═C—H), 7.26 (d, 2H, ArH), 7.36 (d, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:10])[CH2:8][CH3:9])[S:5][CH:6]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:10])[CH2:8][CH3:9])[S:5][CH:6]=1
Reactant: CCC(O)c1cc(Br)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
33.5 g (151 mmol) of 1-(4-bromo-2-thienyl)-1-propanol are dissolved in 400 mL of dichloromethane. 130 g (1.5 mol) of manganese dioxide are then added portionwise and the medium is stirred at room temperature for 24 hours. After filtration through Celite and then concentration and chromatography on silica gel (eluent: 9 heptane/1 ethyl acetate), the desired product is obtained in the form of white crystals (m=26.6 g; Y=80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:22]=[C:23]1[NH:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:25]=[CH:24]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH2:14][N:28]3[C:23](=[O:22])[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:27]3)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: BrCc1cccc(-c2ncc(Br)cn2)n1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(Br)cn4)n3)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2.3 54.6 mg (0.166 mmol) of 5-bromo-2-(6-bromomethylpyridin-2-yl)-pyrimidine and 54.1 mg (0.166 mmol) of caesium carbonate are added to a suspension of 32.7 mg (0.166 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile in 0.5 ml of DMF, and the mixture is stirred for 18 hours at 80° C. The reaction mixture is added to water. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-{1-[6-(5-bromopyrimidin-2-yl)pyridin-2-ylmethyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile as slightly brownish crystals; ESI 445, 447;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17].C(N(CC)CC)C>CN1C(=O)CCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[OH:17])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Temperature: 200 °C

Procedure:
Morpholine (59.9 mg, 0.688 mmol) was added to a solution of 2-bromo-5-nitrophenol (100 mg, 0.459 mmol) and triethylamine (0.070 ml, 0.505 mmol) in NMP. The reaction mixture was heated via microwave irradiation to 200° C. for 1 h. The reaction was monitored by TLC. After completion of the reaction and following cooling, the solvent was removed in vacuo and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) to provide the title compound as a solid. 1H NMR: (CDCl3, 400 MHz): δ 7.82-7.79 (m, 2H), 7.20 (m, 1H), 6.69 (bs, 1H), 3.89 (m, 4H), 2.95 (m, 4H). ESI-MS: 225.1 [M+H]+.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O1CCCC1.Cl>O.CCOCC>[OH:7][C@@H:8]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC1CCCCO1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC[C@H](O)CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 6 h

Procedure:
Di-tert.-butyl 2-[4(S)-(2-tetrahydropyranyloxy)nonyl]-2-(6-ethoxycarbonylhexyl)malonate (47.8 g., 0.08 mole) is added to a mixture of tetrahydrofuran (300 ml.) and 6N hydrochloric acid (15 ml.). The resulting solution is allowed to stand at room temperature for 6 hours. The solution is then diluted with 1.5 liters of water. The oily product is taken up in ether, washed with four portions of water, and with brine and dried over sodium sulfate. Distillation of the ether in vacuo leaves the title compound as a residual oil weighing 39.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1cc(Br)cnc1Cl)S(C)(=O)=O
Yield: 89.4 %

Procedure:
A solution of N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (96 mg, 0.34 mmol, reagent preparation 24) in DMF (1 mL) was treated with potassium carbonate (93 mg, 0.68 mmol) and iodomethane (33 uL, 0.51 mmol) at rt for 18 h. Water was then added, and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous lithium chloride (10%) followed by water, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide N-(5-bromo-2-chloropyridin-3-yl)-N-methylmethanesulfonamide (91.2 mg, 0.304 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, 1H), 8.00 (d, 1H), 3.32 (s, 3H), 3.07 (s, 3H); MS (EI) for C7H8BrClN2O2S: 299, 301, 303 (Br+Cl isotopes, MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH2:23]>CO.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=191-193° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.