Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.Cl.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][CH:31]=[CH:32][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=1>C(OCC)(=O)C>[CH3:6][C:5]1[N:22]([C:23]2[CH:24]=[C:25]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[CH:27][CH:28]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CC(=O)NCCCl
Reactant: CCOC(=O)c1ccoc1-c1cccc(N)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccoc1-c1cccc(N2CCN=C2C)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was added over 10 min to a stirred suspension of phosphorus pentachloride (2.08 g) in ethyl acetate (2 mL) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min at 0° C. toluene (12 mL) was added, and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added in one portion into the above solution at 0–5° C. The mixture was stirred at 0–5° C. for 10 min and then allowed to warm up to 20° C. After 2 h formation of the amidine is essentially complete (HPLC ethyl 2-(3-aminophenyl)-3-furoate hydrochloride <2% @ 220 nm, a/a). The mixture was cooled to 0–5° C., crushed ice (18 g) was added over 20 min to destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) was added at a rate that the internal temperature was kept below 25° C. (ca. 15 min). After 1 h at 20° C. additional ethyl acetate (12 mL) added to the above mixture, the organic layer was separated, washed with deionized water (2×12 mL), and concentrated under reduced pressure. The residue was dissolved in acetone (5 mL) and ethyl acetate (5 mL), and treated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at <20° C. for at least 12 h, the precipitate was collected by filtration, washed with acetone (2×0.5 vol), and dried in vacuo at 45–50° C. to yield 1.9 g (73%) of white solid. 1H NMR (400, d6-DMSO) δ: 8.00 (s, 1H), 7.92–7.90 (m, 2H), 7.64–7.55 (m, 2H), 6.90 (d, 1H), 4.32 (t, 2H), 4.22 (q, 2H), 3.93 (t, 2H), 2.22 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H].ONC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1>[Pd]>[NH2:9][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Solvent: COc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
300 Parts by weight of anisole are mixed with 27 parts of (97%) 1-nitroanthraquinone and 0.2 parts by weight of a palladium/charcoal catalyst (5% of Pd on active charcoal) and heated to 130° in an autoclave. At this temperature, hydrogen is blown through until the rate of up-take of the hydrogen has fallen to 10% of the original value. At this stage, about 2% of overhydrogenation product is present (ascertained by TLC). After interruption of the hydrogen supply, at 130°, 0.4 parts by weight of 1-hydroxylaminoanthraquinone are added and stirring is effected for 30 minutes. The catalyst is separated off at the upper temperature, the filtrate is concentrated and cooled and the 1-aminoanthraquinone is filtered off. No nuclear hydrogenated 1-aminoanthraquinone is present in the mother liquor. 23 Parts of 97% pure 1-aminoanthraquinone is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[C:10]([CH3:11])[C:3]=12.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:44]1([C:50]2[N:51]=[CH:52][NH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN1C(=O)CCC1.C(OCC)(=O)C.[Cu-]=O>[CH3:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[N:53]2[CH:54]=[C:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:51]=[CH:52]2)[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2nccc(Cl)c12
Agent: O=[Cu-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc(-n3cnc(-c4ccccc4)c3)c12
Temperature: 150 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
Compound (97a) (2.00 g), copper(I) oxide (0.048 g), 4,7-dimethoxy-1,10-phenanthroline (0.243 g), cesium carbonate (3.07 g), polyethylene glycol (Mn=3400) (1.35 g), and 4-phenyl-1H-imidazole (1.17 g) were suspended in NMP, followed by stirring at 150° C. for 48 hr. The reaction solution was suspended in ethyl acetate, and insoluble matters were filtered through celite. The filtrate was washed with saturated saline and was then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (97b) (0.272 g, 10%) as a colorless oily substance.
Reaction SMILES: C(O)C.O.[OH-].[K+].[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([O:22]CC)=[O:21])=[CH:19][C:15]=2[C:14]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:13]1)[CH3:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:15]=2[C:14]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:13]1)[CH3:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(NC(=O)c3cccs3)nn(C(C)OCC)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(C)n1nc(NC(=O)c2cccs2)c2cc(C(=O)O)sc21
Temperature: 85 °C
Yield: 29.7 %

Procedure:
1 cm3 of ethanol, 1 cm3 of water and 0.29 g (5.1 mmol) of potassium hydroxide are successively added with stirring to a solution of 1.0 g (2.3 mmol) of ethyl 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylate in 8 cm3 of tetrahydrofuran. The reaction medium is heated at a temperature in the region of 85° C. for 2 hours and is then cooled to a temperature in the region of 25° C. and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified to a pH of about 5-6 by adding solid citric acid, and is then extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 0.25 g of 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid is thus obtained in the form of a yellowish solid. Acidification of the aqueous phase to a pH of about 3-4, followed by the same treatment allows a second fraction of 0.25 g of 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid to be obtained in the form of a yellowish solid. (Rf=0.15, thin-layer chromatography on silica gel, eluent: dichloromethane/methanol (90/10 by volume)).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:25])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(COc1ccc2ccccc2c1)Nc1ccc(C(=O)C(=O)O)cc1
Yield: 90.6 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (2.5 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), faltered, and evaporated to give the crude product. Crystallization from acetone-hexane provided 0.61 g of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid as a colorless solid, mp 215°-216° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1)(=[O:5])=[O:4].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:11][C:10]=2[CH:20]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1O2
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 0.9 g of 10,11-dihydro-N,N-dimethyldibenz[b,f] [1,4]oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3 ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with 5 ml of 2N HCl and three times with 5 ml of 2N Na2CO3. The extract is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and the filtrate concentrated to give 1.1 g of a yellow solid. Crystallization from dichloromethane-diisopropylether gives 0.62 g of crystals, m.p. 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Br)=[N:18][CH:17]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:30])=[N:18][CH:17]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2Br)CC1
Reactant: CB(O)O
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ncc(OCc2cccc(Cl)c2)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A mixture of 3′-bromo-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3j) (82 mg, 0.17 mmol), methylboronic acid (15.3 mg, 0.25 mmol), K3PO4 (72 mg, 0.34 mmol), dppf (4.7 mg, 0.0085 mmol) and PdCl2dppf(CH2Cl2)2 (6.9 mg, 0.0085 mmol) in THF (anhydrous, 1.2 ml) under a nitrogen atmosphere was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of silica gel, eluting with EtOAc-hexane (6:4). The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc-hexane 1:1) to provide 72 mg of the title compound I-3k (>99% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]2(N2CCCC2)[O:8][N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)CC12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc2c1CN(C(C)=O)CC2

Procedure:
A mixture of 18.0 g (58 mmol) of 5-acetyl-7a-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) in 150 mL of DCM and 6.47 mL (87 mmol) of trifluoroacetic acid was heated to reflux for 8 h. After addition of 100 mL of water, the organic phase was dried over MgSO4 and the solvent removed under a vacuum. The remaining brown oil was purified by column chromatography (SiO2, EtOAc/EtOH 10:1). 12.5 g (90% of theoretical) of the desired product 5-acetyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (C) were obtained in the form of a brown-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH2:27][CH2:28][N:29]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:30][CH:31]=3)[CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:16]1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (100.0 mg, 0.18 mmol) prepared in Example 117, triethylamine (74.0 uL, 0.53 mmol) and methanesulfonyl chloride (20.0 uL, 0.26 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 51.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](O)[C:5]([NH:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[C:4]([C:18]#[N:19])[C:3]=1[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[C:6]2[O:17][C:11]([C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[N:10][C:5]2=[C:4]([C:18]#[N:19])[C:3]=1[CH3:20]
Reactant: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)CO)c1C#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Temperature: 25 °C
Yield: 53.5 %

Procedure:
N-(4-Bromo-2-cyano-5-fluoro-6-hydroxy-3-methylphenyl)-3-hydroxy-2,2-dimethyl-1-propanamide (I-107) (1.80 g, 5.21 mmol) was dissolved in toluene (36 ml), pyridinium p-toluenesulfonate (262 mg, 1.04 mmol) was added, followed by heating under reflux for 28 hours. After cooling to room temperature, this was diluted with ethyl acetate, and washed with aqueous sodium hydrogencarbonate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (912.6 mg, 54%) as a white solid. The filtrate was concentrated under reduced pressure to obtain a crude form (514.3 mg, 30%) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:19].[OH-].[K+]>C(O)CCC>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[CH3:19]
Reactant: CCOC(=O)N1CCN(c2cc(C)c(Cl)nn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1cc(N2CCNCC2)nnc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22 parts of ethyl 4-(6-chloro-5-methyl-3-pyridazinyl}-1-piperazinecarboxylate, 28 parts of potassium hydroxide and 160 parts of 1-butanol was stirred overnight at reflux temperature. The reaction mixture was evaporated. Water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 2,2'-Oxybispropane was added. The product was filtered off and dried, yielding 17 parts (100%) of 3-chloro-4-methyl-6-(1-piperazinyl)pyridazine (compound 224).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[CH:7][CH:6]=1.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:37]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOCC>[CH2:42]([O:41][C:39](=[O:40])[CH:38]([C:11](=[O:12])[CH:10]([O:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:14])[C:37]([O:45][CH2:46][CH3:47])=[O:44])[CH3:43]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A 50% etheral solution of 35 g of 2-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-propionyl-chloride is added under stirring dropwise to a mixture of diethyl-ethoxy-magnesium-malonate prepared from 17.6 g of diethyl malonate and 50 ml of ether. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour, cooled to room temperature and washed successively with 100 ml of 5% sulfuric acid, 100 ml of a 6% sodium bicarbonate solution and 100 ml of water. The etheral phase is evaporated, the excess of the malonic acid ester is distilled off, the residue is admixed with 100 ml of benzene, subjected to chromatography on a silica column and eluted with 50 ml of benzene. The united eluates are evaporated. Thus 35 g of the desired compound are obtained in the form of a slowly solidifying product. Mp.: 46°-50° C. Yield 75%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[N:60]([CH2:63][C:64]3[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=3)[CH:61]=[CH:62][C:55]=12.[C:70](=[NH:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:77]1([C:70]([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)=[N:83][C:54]2[C:55]3[CH:62]=[CH:61][N:60]([CH2:63][C:64]4[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=4)[C:56]=3[N:57]=[CH:58][CH:59]=2)[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: Brc1ccnc2c1ccn2Cc1ccncc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(=Nc2ccnc3c2ccn3Cc2ccncc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 25-mL round-bottomed flask equipped with magnetic stirrer and reflux condenser is charged with rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.040 g, 0.063 mmol), Pd2dba3 (0.019 g, 0.021 mmol) and sodium tert-butoxide (0.282 g, 2.94 mmol). The reaction vessel is then purged with a stream of nitrogen for 0.5 h. After such time, a solution of Compound 1b (0.600 g, 2.10 mmol) in toluene (6 mL) followed by benzophenone imine (0.45 g, 2.51 mmol) is added. The reaction is then heated at reflux for 2 h. After such time the reaction is cooled to room temperature and concentrated under reduced pressure. The resulting oil is then purified by column chromatography to afford Compound 1c as a yellow oil.
Reaction SMILES: N1CCOCC1.[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.IC1C=CC(S(Cl)(=O)=O)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[C:34]([S:38]([N:10]2[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]2)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(Br)c2)CC1

Procedure:
Identical procedure to Step A of Example 1, but the morpholine is replaced by tert-butyl piperazine-1-carboxylate and the 4-iodobenzenesulphonyl chloride by 3-bromobenzenesulphonyl chloride.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=1)[CH3:11].Cl[CH2:24][O:25][CH3:26]>ClCCl.CCOCC>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:24][O:25][CH3:26])[CH:15]=1)[CH3:11]
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(OCOC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (5.3 mL, 30.5 mmol) (Aldrich) was added to a suspension of ethyl 3-hydroxy-4-methylbenzoate (5.0 g, 27.75 mmol) (from Example 2 supra) in dichloromethane (20 mL) with cooling in an ice-water bath. Chloromethylmethyl ether (4.2 mL, 55.5 mmol) (Aldrich) was then added dropwise and the mixture stirred at room temperature for 5 hours. The mixture was then diluted with ether (100 mL) and washed with mixture of water (100 mL), followed by 0.1 N HCl (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ether (100 mL). Organic solutions were combined, dried (MgSO4), filtered and concentrated. Residue was filtered through silica gel (Biotage 40 L) eluting with dichloromethane. Fractions were combined and concentrated to give 3-methoxymethoxy-4-methyl-benzoic acid ethyl ester as colorless oil. (Yield 4.88 g, 78.4%).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:11](C(OC(C)(C)C)=O)[NH2:12].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:6][CH2:7][C:8]([NH:11][NH2:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)COC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)COC1CCCC1
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2.60 g of cyclopentyloxyacetic acid (18.03 mmol, 1.0 eq.) are placed in 50 mL of dichloromethane at room temperature with stirring. 2.86 g of tert-butyl hydrazinecarboxylate (21.64 mmol, 1.2 eq.), 2.437 g of hydroxybenzotriazole (18.03 mmol, 1.0 eq.), 4.148 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.64 mmol, 1.2 eq.) and 4.08 mL of diisopropylethylamine (23.44 mmol, 1.3 eq.) are successively added with stirring. After 18 hours, the reaction medium is diluted with dichloromethane and washed twice with water. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 60 mL of dichloromethane. 15 mL of trifluoroacetic acid (201.93 mmol, 11.20 eq.) are added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a dichloromethane/methanol/aqueous ammonia gradient ranging from 99/1/0.1 to 95/5/0.5. 2.7 g of cyclopentyloxyacetic acid hydrazide are obtained.