Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:19][CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCNCCNCNCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
A mixture-of 1,4,7,11,14-penta(p-toluenesulfonyl)-1,4,7,11,14-pentaazacyclopentadecane prepared as in Example 11C (26.3 g, 0.0258 mole) and concentrated H2SO4 (80 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (160 mL) was added dropwise with stirring at 0° C. followed by ethyl ether (400 ml). The resulting tan solid was filtered and dried in vacuo over P2O5. The tarry solid was then dissolved by the addition of 10 N NaOH and the salts were removed by filtration. The solution was then extracted with CHCl3 (6×200 ml). The extracts were combined, dried (Na2SO4) and the solvent was removed in vacuo to give an oil which crystallized on standing. The crude product was dissolved in hexane and insoluble impurities were removed by filtration. Upon cooling to -20° C, 2.28 g (36% yield) of the product was obtained as colorless needles: mp 49-51° C.; 1H NMR (CDCl3) δ 1.69 (m, 4 H), 1.78 (br s, 5 H), 2.76 (m, 20 H). Exact mass: (M+H)+ : calcd., 244. 2501; Found: 244.2557 (C12H30N5).
Reaction SMILES: ClC1C(C2C=CC(O)=C(N)C=2)=NC=C(C(F)(F)F)C=1.[Cl:20][C:21]1[C:22]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][CH:38]([CH3:40])[CH3:39])=[C:33]([N+:41]([O-])=O)[CH:32]=2)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>[Fe]>[NH2:41][C:33]1[CH:32]=[C:31]([C:22]2[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:24][N:23]=2)[CH:36]=[CH:35][C:34]=1[NH:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Product: CC(C)Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Yield: 92.5 %

Procedure:
In a similar manner to the preparation of 3-chloro-2-(3-amino-4-hydroxyphenyl)-5-trifluoromethylpyridine described above, 46.1 g of 3-chloro-2-[4-(1-methylethylamino)-3-nitro-phenyl]-5-trifluoromethylpyridine and 21.5 g of iron powder gave 39.1 g (93%) of colorless crystals; m.p.: 116-117° C.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1.CO.O>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:44])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(C)(C)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(C)(C)C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.4 %

Procedure:
A mixture of chiral 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid methyl ester (21 mg, 0.0327 mmol) was dissolved in THF (3 mL) and methanol (1 mL), followed by 2N LiOH (1 mL). The reaction mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic phase was separated then concentrated under reduced pressure to afford crude product. The compound was purified by RP-HPLC (30%-95% of acetonitrile/water) to afford of chiral 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid (12 mg, 58.4%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H33Cl2F2N3O3+H [(M+H)+]: 628.1940. found: 628.1937.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1.O.[OH-].[Li+].CO.O>C(OCC)C>[C:23]1([C:14]2[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][N:12]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9])[N:13]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCCCC(=O)O
Reactant: Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A mixture of methyl 3,4-diphenyl-1H-pyrazole 1-octanoate (3.40 g, 9 mmol), lithium hydroxide hydrate (1.13 g, 27 mmol), methanol (60 mL), and water (10 mL) was heated at reflux on a steam bath. After 15 minutes, the solution was concentrated in vacuo, diluted with water and 2N HCl solution until pH=1. The mixture was extracted with methylene chloride, the combined extracts dried, and the solvent evaporated to leave an oil. Dissolution in diethyl ether followed by the addition of hexanes provided 3,4-diphenyl-1H-pyrazole-1-octanoic acid (2.80 g, 86%); m.p.=108°-110° C. MS(CI): m/e=363 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran of formula II, ##STR5## is condensed with succinic anhydride in the presence of aluminum chloride in a chlorinated organic solvent and at a temperature below 5° C., to form 4-(2,3-dihydro-5-benzofuranyl)-4-oxobutanoic acid of formula III, ##STR6## which is reduced in acid medium in the heated state and in the presence of zinc and mercuric chloride to form 4-(2,3-dihydro-5-benzofuranyl)butanoic acid of formula IV, ##STR7## which is then subjected to the action of polyphosphoric acid in an apolar organic solvent and at a temperature of between 80° C. and 100° C. to form 2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-8-one of formula V, ##STR8## which is then: either
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(#N)C>CCOCC>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)CCl
Reactant: CCc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCc1cccc(NCC(=O)OC)c1
Reaction time: 48 h
Yield: 46.3 %

Procedure:
To m-ethylaniline (50 g; 0.413 mol) and sodium bicarbonate (69.33 g; 0.825 mol) was added methyl chloroacetate (39.79 ml; 0.454 mol) and acetonitrile (50 ml). The mixture was allowed to heat to 130° with stirring from 48 hours. The mixture was then taken up in ether. The ether extract was treated with 2N hydrochloric acid, after which the acid layer was extracted with ether. The combined organic extracts were washed with water, brine and then dried (Na2SO4). Filtration and evaporation of the solvent gave the title compound (36.95 g: 46%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6]>S(Cl)(Cl)=O.C1CCCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1

Procedure:
A solution of 2,6-dichloroisonicotinic acid (38.4 g, 0.20 mole) in thionyl chloride (60 ml.) and cyclohexane (100 ml) containing a few drops of dimethylformamide is heated at 80° for three hours. The solution is cooled and excess thionyl chloride and cyclohexane are removed in vacuo. The residue is dissolved in chloroform (40 ml.) and added dropwise to a solution of t-butanol (50 ml.) and N,N-dimethylaniline (40 ml.). The solution is heated at reflux for six hours, cooled, diluted with diethyl ether and washed successively with water, water containing 4 ml. of concentrated sulfuric acid, water, dilute sodium carbonate solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residue is crystallized from a minimum amount of methanol to give 24 g. of product, m.p. 79°-81°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1([F:25])[C:14]([F:16])(I)[C:13]([F:18])([F:17])[C:12]([F:20])([F:19])[C:11]([F:22])([F:21])[C:10]1([F:24])[F:23].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(OC)(C)(C)C.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:8][C:9]1([F:25])[C:14]([F:16])([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:13]([F:18])([F:17])[C:12]([F:19])([F:20])[C:11]([F:21])([F:22])[C:10]1([F:23])[F:24]
Reactant: FC1(F)C(F)(F)C(F)(F)C(F)(I)C(F)(F)C1(F)F
Reactant: Nc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ccc(C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C2(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
Aniline (1.0 g) was dissolved in tert-butylmethyl ether (15 ml) and water (15 ml), and added with undecafluoroiodocyclohexane (5.5 g), sodium dithionite (2.3 g), sodium hydrogen carbonate (1.1 g) and tetrabutylammonium hydrogen sulfate (0.46 g) in order. The resulting mixture was stirred vigorously at room temperature for 18 hours. After separating the reaction solution, the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed with 2N hydrochloric acid and sodium hydrogen carbonate solution in order, and dried over anhydrous magnesium sulfate, The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 4-(undecafluorocyclohexyl)aniline (2.7 g, yield 68%).
Reaction SMILES: [C:1]([N:4]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][C:6]([NH:12][C:13]2[C:18](Br)=[CH:17][N:16]=[C:15]([C:20]3[S:24][C:23]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:27])=[O:26])=[CH:22][CH:21]=3)[N:14]=2)=[N:5]1)(=[O:3])[CH3:2].CCN(CC)CC.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([N:4]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][C:6]([NH:12][C:13]2[C:18]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:17][N:16]=[C:15]([C:20]3[S:24][C:23]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:27])=[O:26])=[CH:22][CH:21]=3)[N:14]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2Br)cc1C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2C#C[Si](C)(C)C)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (from step 4), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) and CuI (8 mg, 0.04 mmol, 0.1 eq) was flushed with nitrogen. Anhydrous THF (12 mL) and Et3N (121 mg, 1.2 mmol, 3.0 eq) were added and the reaction mixture was flushed with nitrogen. Ethynyl-trimethylsilane (118 mg, 1.2 mmol, 3.0 eq) was added and the reaction mixture was stirred at rt for 1 h. Then, the reaction mixture was concentrated to about 5 mL, which was taken in EtOAc and was washed with water, brine. The combined organic layers were concentrated to afford crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)-N-(2-(dimethylamino)ethyl) thiophene-2-sulfonamide, which was used for the next step without further purification). LC-MS (m/z)=572.0 [M+H]+
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][O:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:37][C:38]1[C:43](O)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]>O1CCCC1>[F:37][C:38]1[C:43]([O:33][C:32](=[O:34])[CH2:31][NH:30][C:28](=[O:29])[C:27]2[CH:35]=[CH:36][C:24]([O:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(OCc2ccccc2)cc1)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
N-(4-(Phenylmethoxy)benzoyl)glycine pentafluorophenyl ester. N-(4-(Phenyl-methoxy)benzoyl)glycine methyl ester (14.75 g, 49.2 mmol) was boiled under reflux with methanolic sodium hydroxide (1M) (80 mL) for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in water and was acidified by addition of aqueous hydrochloric acid. The suspension was extracted with ethyl acetate. The extract was washed with saturated brine and was dried with anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine (6.59 g, 47%). Dicyclohexylcarbodiimide (720 mg, 3.5 mmol) was added to N-(4-(phenylmethoxy)benzoyl)glycine (100 g, 3.5 mmol) in dry tetrahydrofuran (100 mL) and the mixture was taken to 0° C. Pentafluorophenol (640 g, 3.5 mmol) was added dropwise and the mixture was stirred for 17 h at 0° C. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and was washed with saturated aqueous sodium hydrogen carbonate (2×75 mL), with aqueous sulphuric acid (10%) and with water. The solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine pentafluorophenyl ester (Intermediate B) (1.5 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:9])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: CC(C)N
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
The product was prepared from 5,6-dichloro-nicotinic acid (0.86 g), carbonyldiimidazole (0.8 g) and isopropylamine (0.52 ml) using the method of example 115 step (i). Yield 0.69 g.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=C/CCCCCCC.[C:13]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:26][CH2:25]1)(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:13]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:1][CH3:2])=[O:33])[CH2:26][CH2:25]1)(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCC/C=C/C(=O)N1CCN(CCC(=O)O)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(CCC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 3-piperazin-1-yl propionate dihydrochloride (ethyl ester of Compound 21) as starting raw materials, to produce ethyl 3-[4-((E)-2-decenoyl)piperazin-1-yl]propionate, and subjected to alkali saponification, to obtain an intended compound as white crystals. White crystals, mp 53°-55° C., C17H30N2O3 MW 310.4, EIMS: m/z 311 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J=7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.35-1.44 (m, 2H), 2.12-2.20 (m, 2H), 2.32-2.43 (m, 6H), 2.55-2.61 (m, 2H), 3.43-3.57 (m, 4H), 6.45 (d, J=15.0 Hz, 1H), 6.65 (dt, J=15.0, 7.0 Hz, 1H), 11.70-12.70 (brs, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=4[CH:12]=3)=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: OCc1cc2cc(I)ccc2o1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: OCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2o1

Procedure:
Prepared according to general working method I from (5-iodo-benzofuran-2-yl)-methanol (685 mg, 2.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (534 mg, 2.50 mmol).
Reaction SMILES: S(=O)(=O)(O)O.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[O:20]C(=O)C)(=O)C.[C:24](OCC)(=O)[CH3:25]>>[CH3:24][C:25]1[C:14]2[C:13](=[CH:12][C:11]([OH:20])=[C:10]([OH:9])[CH:15]=2)[O:16][C:17](=[O:19])[CH:18]=1
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)oc2cc(O)c(O)cc12
Yield: 95 %

Procedure:
45 ml 75% sulphuric acid is added dropwise to a mixture of 5.8 ml ethyl acetate and 11.4 g 1,2,4-triacetoxy- benzene, heated for 30 min to 80° C., poured onto ice, filtered, the precipitate is washed neutral and dried in a vacuum. 8.2 g of the title compound (95 % of theory) is obtained with a melting point of 270° to 272° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:24])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[O:11]1.O>CN(C=O)C>[Br:1][C:21]1[CH:22]=[C:17]([B:12]2[O:11][C:10]([CH3:24])([CH3:9])[C:14]([CH3:15])([CH3:16])[O:13]2)[C:18]([NH2:23])=[N:19][CH:20]=1
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2cc(Br)cnc2N)OC1(C)C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
N-Bromosuccinimide (255 mg) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg) in DMF (6.8 ml) at room temperature, and the mixture was stirred for four hours. Water was added and the precipitated solid was collected by filtration to give 210 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.Cl>CO>[NH2:8][C:5]1[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1NS(C)(=O)=O
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cc(Br)cnc1N

Procedure:
A solution of tert-butyl 5-bromo-3-(methylsulfonamido)pyridin-2-ylcarbamate (57 mg, 0.15 mmol) in methanol (1 mL) and HCl (4 M in dioxane, 375 uL, 1.5 mmol) was heated to 60° C. for 90 min. The volatile materials were then removed in vacuo to provide N-(2-amino-5-bromopyridin-3-yl)methanesulfonamide as its hydrochloride salt in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (br s, 1H), 7.95 (d, 1H), 7.54 (d, 1H), 6.42 (br s, 1H), 3.02 (s, 3H); MS (EI) for C6H8BrN3O2S: 266, 268 (Br isotopes, MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[S:4][C:3]=1C(OC)=O.CN1CCNCC1>CN1CCCC1=O>[N+:11]([C:10]1[C:5]2[S:4][CH:3]=[C:2]([NH2:1])[C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:13])=[O:12]
Reactant: COC(=O)c1sc2c([N+](=O)[O-])cccc2c1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: Nc1csc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A mixture of 4.82 g (19.1 mmol) methyl 3-amino-7-nitro-1-benzothiophene-2-carboxylate (WO 9738983), 1-methyl-2-pyrrolidinone (23 mL) and 1-methylpiperazine (6.5 mL) is stirred at 185–190° C. for 4 hours, then cooled to room temperature. The precipitate is filtered, washed with diethyl ether, and dried to give 7-nitro-1-benzothiophen-3-amine (3.3 g, 89%) as a red-brown solid, m.p. 188–191° C.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])=[CH:13][C:8]=2[O:7][CH2:6]1>CO>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35](=[O:1])[NH2:36])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C(N)=O)C1
Yield: 57 %

Procedure:
0.5 ml of hydrogen peroxide (33%) and 0.2 ml of 2N sodium hydroxide solution were added to a solution of 236 mg (0.54 mmol) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-cyano-benzyloxy)-piperidine1-carboxylate in 5 ml of methanol. The reaction solution was heated under reflux for 2 hours. Subsequently, the same amounts of hydrogen peroxide and sodium hydroxide solution were again added and the solution was heated for a further 2 hours. Thereafter, the solution was cooled and evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. There were obtained 140 mg (57% of theory) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-carbamoyl-benzyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 455 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:23][CH:24]([F:26])[F:25])=[C:15]2[O:19][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]=12)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:25][CH:24]([F:26])[O:23][C:14]1[C:15]2[O:19][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]=2[C:11]([C:9]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1cc2c(C(=O)Nc3ccncc3N)ccc(OC(F)F)c2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc2c(-c3nc4cnccc4[nH]3)ccc(OC(F)F)c2o1

Procedure:
1.8 g of N-(3-aminopyrid-4-yl)-7-difluoromethoxy-2-(1-methylethyl)benzofuran-4carboxamide are boiled with 4.0 g of p-toluenesulfonic acid in 50 ml of toluene for 3 h in a water separator. The cooled solution is extracted by shaking with 50 ml of 2 N sodium hydroxide solution, the separated aqueous phase is extracted a further two times with 50 ml of ethyl acetate each time, and the organic phases are combined, dried over ignited potassium carbonate and concentrated in vacuo. The residue is crystallized from ethanol/water. 1.7 g (100% of theory) of the title compound of m.p. 201° C. are obtained.