Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([I:18])=[C:14](Cl)[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Na].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:23]([O:24][C:2]1[N:17]=[CH:16][C:15]([I:18])=[C:14]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:22]1[CH:21]=[CH:25][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(OCc1ccccc1)c1c(Cl)ncc(I)c1Cl
Reactant: C1CCOC1
Agent: [Na]
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(I)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Into a solution of benzyl 2,4-dichloro-5-iodonicotinate (3.7 g, 9.1 mmol) in THF (20 mL) was added a solution of sodium benzoxide in THF (1.0 M×20 mL, 20 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-iodonicotinate (2.55 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:12](OC)=[O:13])[CH3:10])=[CH:5][CH:4]=1>C(Cl)Cl.C1CCCC=CCC1.C1CCCC=CCC1.C1CCCC=CCC1.C1CCCC=CCC1.[Cl-].[Cl-].[Ir].[Ir]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH:12]=[O:13])[CH3:10])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Agent: [Ir]
Agent: C1=CCCCCCC1
Agent: C1=C\CCCCCC/1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C)[C@@H](C=O)CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-methyl 2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanoate (6.00 g, 19.5 mmol) and chlorobis(cyclooctene)-iridium(I) dimer (0.349 g, 0.389 mmol) in dry DCM (19.5 mL) was slowly added Et2SiH (3.76 mL, 29.2 mmol) at 0° C. The flask was removed from the cold bath and the reaction was stirred at room temperature for 20 h under nitrogen (N2). The reaction mixture was transferred via cannula to an ice-cooled mixture of diethyl ether (Et2O; 60 mL) and 2 Normal (N) HCl (20 mL) over 15 min. The mixture was removed from the cold bath and stirred at room temperature for 30 min. The phases were separated and the aq. phase was further extracted with Et2O (2×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (NaHCO3; 25 mL) and brine (25 mL), dried over Na2SO4, filtered, and the filtrate treated with Celite® (5 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (120 g SiO2, 0→75% EtOAc/hexanes) to afford the intermediate aldehyde, (S)-2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanal.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].Cl>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:22]([N+:31]([O-:33])=[O:32])[CH:23]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
5 g of 4-(2-benzenesulfonylaminoethyl)phenoxyacetic acid are added to 30 ml of acetic anhydride, and 3 ml of a mixture of conc. nitric acid and acetic acid (1:2) are added thereto under ice-cooling and stirring. After the mixture is reacted for 4 hours at room temperature, the mixture is poured into a mixture of diluted hydrochloric acid and ice, extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform: ethanol=60:1) and recrystallized from a mixture of ethyl acetate and n-hexane. 3.70 g of 4-(2-benzenesulfonylaminoethyl)-2-nitrophenoxyacetic acid are obtained as colorless needles.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[N:29]=[CH:28][CH:27]=[N:26]1.Cl[C:32]1[CH:37]=[N:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1>C1COCC1>[N:29]1[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[O:11][C:32]2[CH:37]=[N:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)=[O:30])[N:26]=[CH:27][CH:28]=1
Reactant: O=C(N[C@H]1CCC[C@H]1O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCC[C@H]1Oc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS in THF (1.0 M, 0.477 ml, 0.477 mmol) was added to a solution of N-[(1S,2R)-2-hydroxycyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 10; 0.100 g, 0.37 mmol) in THF (3 ml) at 0° C. under nitrogen. The reaction was stirred at this temperature for 1 hour and then 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 0.059 ml, 0.48 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction was then quenched with water (2 ml) and extracted with ethyl acetate (30 ml). The organics were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCC
Reactant: O=[PH2][O-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC[PH](=O)O
Yield: 82.1 %

Procedure:
To a mixture of 95.2 g (0.898 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-hexene (25.2 g, 0.30 mol) was added to the stirred mixture followed by 1.76 g (0.0155 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.14 g (0.0101 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 37.0 g n-hexylphosphinic acid (82.4% yield) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[CH:25]([NH2:28])([CH3:27])[CH3:26].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:28][CH:25]([CH3:27])[CH3:26])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)C)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (970 mg, 2.5 mmol), isopropylamine (1 mL, 12.5 mmol), copper(I) iodide (285 mg, 1.5 mmol), N,N-dimethylglycine hydrochloride (280 g, 2 mmol), and potassium carbonate (3.455 g, 25 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-isopropylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (915 mg, 90%) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C23H30N2O2 (M+H)+: 367.51, observed: 367.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:24]3[CH2:25][CH2:26][C:21]([F:20])([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: FC1(c2ccccc2)CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 67.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.55 g, 6.18 mmol) obtained in Example 19, step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (2.0 g, 9.27 mmol), the title compound (1.72 g, 68%) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([SH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].N1CCCCC1>CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([S:17][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(S)cc1F
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1F
Temperature: 105 °C
Yield: 101.1 %

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (1.23 g, 12.33 mmol), 3-fluoro-4-methoxy thiophenol (Compound 200, 1.95 g, 12.33 mmol), and piperidine (314.8 mg, 3.70 mmol). This mixture was heated to 105° C. for 23 hours, cooled to room temperature and dissolved in EtOAc (100mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded 3.22 g of a clear yellow oil which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ: 7.32 (2H, m), 6.94 (1H, t, J=8.4 Hz), 3.92 (3H, s), 2.54 (2H, s), 1.41 (6H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:17]1([S:23]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
N,N′-carbonyldiimidazole (14.45 g) was added to a solution of 10.00 g of 4-acetylamino-3-nitrobenzoic acid in 300 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, 14.03 g of benzenesulfonamide and 13.58 g of diazabicycloundecene were added thereto, and the mixture was stirred at 100° C. for 72 hours. The reaction mixture was separated with the addition of chloroform and water. The organic layer was then concentrated, and the resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 12.67 g of N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CCN(S(F)(F)[F:33])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([F:33])([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(F)cc2)C1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(F)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled stirred solution of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (500 mg, 1.3 mmol) in DCM (50 mL) was dropwise added DAST (443 mg, 2.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (50 mL), washed with saturated sodium bicarbonate solution (3×30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified with reverse phase HPLC to yield 8-chloro-5-(2-fluoro-2-(4-fluorophenyl)propyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole. 1H-NMR (DMSO-d6, oxalate salt) δ (ppm): 7.50 (s, 1H), 7.40 (m, 3H), 7.18 (t, 2H), 7.05 (d, 1H), 4.60 (m, 2H), 4.25 (m, 2H), 3.05 (m, 2H), 2.85 (s, 3H), 2.70 (m, 2H), 1.65 (d, 3H). Separation by chiral HPLC provides enantiomers II-211a-b.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH3:4].[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH2:17]>C(#N)C>[CH3:1][C:2]12[C:3]3([CH3:4])[N:14]([CH2:13][CH2:12][CH2:11][N:10]3[CH2:9][CH2:8][NH:7]1)[CH2:15][CH2:16][NH:17]2
Reactant: NCCNCCCNCCN
Reactant: CC(=O)C(C)=O
Solvent: CC#N
Product: CC12NCCN3CCCN(CCN1)C32C

Procedure:
A solution of 5.37 g (62.4 mmol) of butanedione in 30 ml of acetonitrile is slowly added dropwise to a solution of 10.00 g (62.4 mmol) of commercial N,N′-bis (2-aminoethyl)-1,3-propanediamine in 100 ml of acetonitrile at 0° C. The mixture is maintained at this temperature for two hours. After evaporating the solvent, compound 1 is isolated quantitatively in the form of a yellow solid and is used for the following stage without subsequent purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O-:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O>C1COCC1>[C:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)Oc1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
4-Pentenoyl chloride (8.16 g, 69.1 mmol) was added dropwise to sodium phenoxide (8.02 g, 69.1 mmol) in THF (160 ml) at 20° C. After 24 hours at 20° C. H2O (100 ml) was added and the aqueous phase was extracted with Et2O (3×200 ml). The organic phase was washed with NaHCO3 (2×200 ml), brine (2×200 ml) to neutrality, then dried (Na2SO4), filtered, concentrated and bulb-to-bulb distilled to afford the desired title ester in 90% yield. B.p.: 70° C./0.04 mbar.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])C=1>>[CH3:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2ccccc2)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Agent: [I-]
Product: Cc1c(-c2ccccc2)c(=O)oc2cc(OC(=O)N3CCOCC3)ccc12
Yield: 41.1 %

Procedure:
The title compound (75 mg, 41% yield, crystals) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)O)P(O)(C(C)(C)C)C(C)(C)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:16]2[S:15][C:19]([C:2]3[N:7]=[C:6]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[CH:18][N:17]=2)[CH:21]=1
Reactant: c1cncc(-c2nccs2)c1
Reactant: CC(=O)NS(=O)(=O)c1cccc(Br)n1
Agent: CC(C)(C)[PH](O)(C(C)(C)C)[Pd](Cl)(Cl)[PH](O)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cnc(-c3cccnc3)s2)n1

Procedure:
N-[(6-Bromopyridin-2-yl)sulphonyl]acetamide (0.112 g, 0.4 mmol), 3-(1,3-thiazol-2-yl)pyridine (0.065 g, 0.4 mmol, prepared by the methods described in WO 2010/006713), dichloro{bis[di-tert-butyl(hydroxy)phosphoranyl]}palladium (0.006 g, 0.012 mmol) and caesium carbonate (0.26 g, 0.8 mmol) were stirred in 10 ml of N,N-dimethylformamide at 120° C. under argon for 16 h. After cooling, the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, dichloromethane/methanol eluent). This gave 0.024 g (15% of theory) of N-({6-[2-(pyridin-3-yl)-1,3-thiazol-5-yl]pyridin-2-yl}sulphonyl)acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[F-:10].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cl)cn1
Reactant: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cn1
Yield: 48.2 %

Procedure:
A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue afforded 425 mg (48%) of 2-cyano-5-fluoropyridine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[CH:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:13]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-4-methoxy-1-nitro-benzene (84.1 g, 0.49 mol) and dimethyl malonate (129.9 g, 0.98 mol) in DMF (490 ml), potassium carbonate (135.9 g, 0.98 mol) is added at ambient temperature. The reaction mixture is stirred at 70 C.° for 12 h. The reaction mixture is added to toluene (393 ml) and 12 N HCl (123 ml) and extracted with ethyl acetate. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 2-(5-methoxy-2-nitro-phenyl)-malonic acid dimethyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1.Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[NH:25][N:24]=[C:23]2[Cl:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>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].CC(N(C)C)=O>[Cl:31][C:23]1[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH:5]=3)[CH:21]=2)[C:26](=[O:30])[NH:25][N:24]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(NCCN2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(NCCN4CCOCC4)c3)ccc12
Temperature: 85 °C
Yield: 21.1 %

Procedure:
A mixture of (3-aminomethyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine hydrochloride (212 mg, 0.781 mmol), 6-bromo-4-chloro-2H-phthalazin-1-one (184 mg, 0.710), Pd2(dba)3 (65 mg, 0.071 mmol), rac-BINAP (142 mg, 0.228 mmol), NaOtBu (266 mg, 2.768 mmol) and DMA (5 mL) was heated to 85° C. until the reaction was completed by HPLC. The reaction was filtered through celite and purified by preparatory HPLC to yield 4-chloro-6-[3-(2-morpholin-4-yl-ethylamino)-benzylamino]-2H-phthalazin-1-one hydroformate (62 mg) as a light brown solid. 1H (400 MHz, d6-DMSO) δ: 2.29 (m, 4H), 2.36 (t, 2H), 3.02 (m, 2H), 3.48 (m, 4H), 4.24 (d, 2H), 5.38 (bs, 1H), 6.40 (dd, 1H), 6.47 (d, 1H), 6.51 (s, 1H), 6.77 (s, 1H), 6.97 (t, 1H), 7.07 (dd, 1H), 7.54 (t, 1H), 7.85 (d, 1H), 8.10 (s, 1H), 12.26 (s, 1H) ppm; m/z (M+1) 413.93.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([C:8]([N:10]1[CH2:18][CH2:17][N:16]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=O)[CH2:15][CH2:14][N:13]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=O)[CH2:12][CH2:11]1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.C1COCC1.[OH-].[Na+]>CO>[CH2:8]([N:10]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:14][N:13]([CH2:28][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:12][CH2:11]1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC(=O)N1CCN(C(=O)CCCCCCC)CCN(C(=O)CCCCCCC)CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCN1CCN(CCCCCCCC)CCN(CCCCCCCC)CC1
Temperature: 25 °C
Yield: 85 %

Procedure:
All of the 1,4,7-tri(n-heptylcarbonyl)-1,4,7-triazacyclononane was put into a 200 mL three neck flask provided with a reflux tube in an argon atmosphere, and a BH3.THF solution (100 mmol, 100 mL) was added thereto and reflowed for one night. To break down the excess BH3.THF, methanol was added slowly to the reaction mixture after allowing it to cool to room temperature, and after concentration, this was dissolved in 1-butanol (50 mL), water (50 mL) and concentrated hydrochloric acid (100 mL and reflowed for one night. The reaction mixture obtained was cooled in an ice bath, and a 48% aqueous solution of sodium hydroxide was added until the pH exceeded 12. After amine separation, this aqueous solution was extracted in methylene chloride (8×50 mL). After the organic layer that was obtained was dried using anhydrous sodium sulfate, it was concentrated, and pale yellow, oily 1,4,7-tri-n-octyl-1,4,7-triazacyclononane (2.45 g, 85% yield) was obtained.