Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Cl)[CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCl
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
100.0 mg of compound (6) was dissolved in 0.8 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 10 mg of sodium hydride under cooling with ice. After 15 minutes, 44 μl of hexyl chloride was added, and the reaction solution was stirred under cooling with ice for 2 hours. The reaction solution was allowed to react at room temperature for another 90 minutes under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×21 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 18.7 mg of compound (45) as a colorless oily substance.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:30]([CH3:29])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Reactant: CNC1CCOCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1)C1CCOCC1
Temperature: 160 °C
Yield: 26 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.14 mmol) and methyl(tetrahydro-2H-pyran-4-yl)amine (31 mg, 0.27 mmol) were dissolved in DMSO (0.5 ml) in a microwave vial. DIPEA (0.141 ml) was added and the mixture was heated at 160° C. for 4 h under microwave irradiation. The reaction mixture was diluted with MeOH (0.5 ml) and was purified by Mass Directed Automated Preparative HPLC (Method C). Fractions containing product were blown to dryness and the residue dissolved in methanol. This solution was loaded onto a 1 g aminopropyl column which was eluted with MeOH (1 column volume). The solvent was removed under a stream of nitrogen to give the title compound (17 mg) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([NH2:18])([CH3:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.ClCCl>CO>[CH3:1][O:2][C:3]([C:4]1([CH3:17])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:7]=2[CH:24]([C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([OH:20])[CH:22]=2)[NH:18]1)=[O:19]
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccc(OC)cc12
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Temperature: 25 °C
Yield: 15 %

Procedure:
To a solution of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (5.178 g, 19.5 mmol) and 3-hydroxybenzaldehyde (2.85 g, 23.4 mmol, 1.2 equiv.) in dry dichloromethane (80 ml) trifluoroacetic acid (1.5 ml, 19.5 mol, 1 equiv.) is added and the mixture is stirred under argon at room temperature. When TLC indicates the disappearance of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (1 day), a little methanol is added to dissolve the product precipitated during the reaction. The mixture is then diluted with dichloromethane (750 ml) and is washed with 2 M aqueous HCl, aqueous NaHCO3 and water, is dried and concentrated. Column chromatography (dichloromethane-ethyl acetate 9:17:1) of the residue gives 5.22 g (73%) of (1RS,3SR)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 183-184° C. from ethyl acetate-light petroleum) and 1.07 g (15%) of (1RS,3RS)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 175-177° C. from ethyl acetate-light petroleum).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[CH2:1]([C:3]1[C:4]([O:13][CH2:23][O:24][CH3:25])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(C)c(C(=O)O)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C)c(C(=O)O)c1OCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol) and diisopropylethylamine (13.2 ml, 76 mmol) in dry dichloromethane (30 ml) was cooled in an ice-bath. Chloromethyl methyl ether (3.83 ml, 50.6 mmol) was added slowly and the mixture was allowed stand at 0° C., warming slowly to room temperature. After 36 h a further portion of chloromethyl methyl ether (1.9 ml) was added and the mixture was left at room temperature overnight. The mixture was then washed with 10% citric acid, water and brine, dried and evaporated to give the title compound (6.34 g, 100%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:12]([Cl:13])=[C:11]([CH:14]([F:16])[F:15])[N:10]=[CH:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][C:7]1[C:12]([Cl:13])=[C:11]([CH:14]([F:16])[F:15])[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc(C(F)F)c1Cl
Solvent: Cc1ccccc1
Product: FC(F)c1ncnc(Cl)c1Cl

Procedure:
100 ml of POCl3 was added dropwise to a solution of 65.0 g (0.36 mol) of 4-hydroxyl-5-chloro-6-(difluoromethyl)pyrimidin in 150 mL of toluene, the mixture was refluxed for 3-5 h after addition. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove toluene and extra POCl3, and then poured into ice water. The water phase was extracted with ethyl acetate (3×50 ml), the organic phases were emerged, washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column to give 64.5 g as yellow liquid, cooled to be solid in refrigerator with yield of 90%.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(O)(=O)C.Br([O-])(=O)=O.[Na+]>O>[CH:3]1[C:4]([CH:7]=[O:8])=[CH:5][CH:6]=[C:1]([CH:9]=[O:10])[CH:2]=1
Reactant: OCc1ccc(CO)cc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(C=O)cc1

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.55 g (4 mmols) of p-xylylene glycol was used in place of m-methoxybenzyl alcohol and 1 ml (17.4 mmols) of acetic acid was used in place of 2 ml of acetic acid, and also 1 ml of water and 0.4 g (2.7 mmols) of sodium bromate were used. With respect to the components in the reaction solution, the intended p-phthalaldehyde was produced in an area ratio, as determined by gas chromatography, of 56.0% and p-hydroxymethylbenzaldehyde as a product at the intermediate stage (compound in which only one among two hydroxymethyl groups in a molecule of the raw material was replaced by a formyl group) was produced in an area ratio of 28.6%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22]>[Cu]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[C:13]([F:22])=[C:14]([F:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=2[F:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]
Product: O=[N+]([O-])c1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 190 °C
Yield: 63.4 %

Procedure:
A mixture of 4-iodonitrobenzene (15 g, 0.060 mol), bromopentafluorobenzene (14.9 g, 2.56 mL, 0.060 mol) and copper powder (30 g) was placed into a 50-mL J-Young glass tube and heated at 190° C. for 24 hours. The tube was cooled and the mixture was extracted exhaustively with dichloromethane. The solvent was removed and the residue was extracted with boiling hexane and filtered while hot. The solvent was removed and the resulting viscous solid was sublimed to obtain 4-nitro-2′,3′,4′,5′,6′-pentafluorobiphenyl as a yellow solid (11.0 g, 63% yield).
Reaction SMILES: [C:1]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([F:13])[F:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([O-:21])([OH:20])=[O:19].[Na+:22].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[F:13][C:11]([F:12])([S:18]([O-:21])(=[O:20])=[O:19])[CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([F:16])([F:15])[F:17].[Na+:22]
Reactant: O=C(OC(=C(F)F)C(F)(F)F)c1ccccc1
Reactant: O=S([O-])O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Reaction time: 65 h
Yield: 43 %

Procedure:
10.0 g of 1,1,3,3,3-pentafluoropropen-2-yl benzoate which had been synthesized by a conventional technique, was dispersed in 72 g of water, after which 12.0 g of sodium hydrogen sulfite and 1.24 g of benzoyl peroxide were added. Reaction occurred at 85° C. for 65 hours. The reaction solution was allowed to cool, after which toluene was added, followed by separatory operation to separate a water layer. A saturated sodium chloride aqueous solution was added to the water layer whereupon white crystals settled out. The crystals were collected by filtration, washed with a small volume of saturated sodium chloride aqueous solution and then dried in vacuum, obtaining the target compound, sodium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate. White crystals, 5.85 g (yield 43%).
Reaction SMILES: [C:1]1(S([O:10][CH2:11][CH2:12][CH2:13]CCCCCCCCC)(=O)=O)C=CC=CC=1.[Na].[C:24]([O:27][CH:28]=[CH2:29])(=[O:26])[CH3:25]>O>[C:24]([O:27][CH:28]=[CH2:29])(=[O:26])[CH3:25].[C:11]([OH:26])(=[O:10])[CH:12]=[CH2:13].[C:24]([O:27][CH3:28])(=[O:26])[CH:25]=[CH2:1]
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: C=COC(C)=O
Product: C=CC(=O)O
Product: C=CC(=O)OC
Temperature: 10 °C

Procedure:
A 19:6:75 mole ratio poly(vinyl acetate/acrylic acid/methyl acrylate) was synthesized in the following manner. In a liter polymerization flask fitted with baffles, 295.0 g of deionized water, 10.34 of nonylphenol ethoxylate sulfate ammonium salt (58% solution), available from Rhone-Poulenc of Cranbury, N.J., 9.02 g of sodium dodecyl benzene sulfonate (23% solution) available from Rhone-Poulenc of Cranbury, N.J., 2.0 of EO-PO block copolymer available from BASF, Mt. Olive, N.J. were taken and a solution was effected by mixing. To the resultant clear solution, 0.19 g of SAG 2001, an antifoam available from Witco of Greenwich, Conn. and vinyl acetate (99%) 40.8 g was added, nitrogen was sparged through the solution for 15 minutes and the solution was cooled down to 10° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])(=[S:56])C.C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[SH:56][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CC([O-])=S
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCc2c(S)cccc21
Temperature: 120 °C
Yield: 54 %

Procedure:
4-Bromo-indanone (500 mg, 2.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (137 mg, 0.24 mmol), thioacetate (541 mg, 4.74 mmol) and diisopropylethylamine (1.64 mL, 5.69 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2 and tris(dibenzylideneacetone)palladium(0) (217 mg, 0.24 mmol) is added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 210 mg). LC (METHOD 5): tR=0.89 min; Mass spectrum (ES−): m/z=163 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C=O)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(CO[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93.9 %

Procedure:
A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.00 g, 10.7 mmol) in anhydrous DMF (12 ml) was added dropwise to a stirred slurry of sodium hydride (60% dispersion in oil, 0.465 g, 11.6 mmol) in DMF (25 ml) at -10° C. under nitrogen and the mixture stirred at this temperature for 0.67 h. 4-Methoxybenzyl chloride (1.52 ml, 11.2 mmol) was added dropwise and the mixture warmed to 0° C. over 1 h and then stirred at RT for 2 h. Water was added and the mixture poured into ether and washed with water (×3). The ethereal layer was dried (MgSO4), evaporated in uacuo and the crude product chromatographed on silica gel, eluting with ethyl acetate/hexane (30:70), to afford the title pyrrolidine (3.09 g, 94%),δ (250 MHz, CDCl3) 1.46 (9H, br s, OC(Me)3), 1.73-2.09 (2H, m, CH2), 3.40-3.46 (4H, m, 2 of CH2), 3.81 (3H, s, OMe), 4.12 (1H, m, CHOCH2Ar), 4.45 (2H, s, OCH2Ar), 6.85-6.91 (2H, m, Ar--H), 7.23-7.27 (2H, m, Ar--H).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([O:43]CC)=[O:42])=[CH:39][N:40]=1.[OH-].[Li+].C1COCC1>O.CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:36]1[N:37]([C:46]2[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=2)[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=1
Reactant: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-((2-Chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (43) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42) (44 mg, 0.11 mmol), lithium hydroxide (11 mg, 0.46 mmol), THF (0.1 mL), methanol (0.2 mL), and water (0.4 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.070 g, 29% yield). LCMS: 557.40 (M+1)+; HPLC % 98.83 (@ 254 nm) (Rt; 4.303; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H, J=4 Hz), 7.56 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=8 Hz), 7.28 (s, 1H), 7.13 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.57 (m, 4H), 3.48 (s, 2H), 2.74 (t, 1H), 2.64 (s, 3H), 2.36 (m, 4H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69-1.71 (m, 3H), 1.53-1.56 (m, 2H), 1.41-1.44 (m, 2H), 1.10-1.23 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].C([OH:15])C.C([O-])=O.[Na+]>O.C(O)=O>[OH:15][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: CCO
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A 1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 45 g of 4-chloroacetyl-catechol of a purity of ca. 90%, 260 ml of ethanol, 130 ml of water, 38 g of sodium formate and 17 ml (˜21 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 24 hours. Under vacuum a part of the solvents was distilled off. The remaining solution of about 100 ml was acidified by addition of 35.5 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. 200 ml of water were added and the mixture was refluxed for 10 minutes. Upon stirring over night without heating crystals separated. The slurry was filtered by suction and the crystals were washed with 50 ml of cold water. After drying over night at 70° C. at ˜20 mbar the yield of 4-hydroxyacetyl-catechol was 34.2 g with a purity of 89.2% corresponding to a yield of 82.6%. In the mother liquors additional 14% of the product was detected by analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[NH4+:15].[OH-]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)CCCc1ccc(N)cc1
Yield: 70 %

Procedure:
To a solution of compound 27 (300 mg, 1.55 mmol) in CH3OH (5 mL) was added NH4OH (32) at room temperature with stirring. The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. The residue was diluted with water and extracted with DCM/CH3OH (10:1). The combined organic layers were dried over Na2SO4 and concentrated to dryness to give compound 33 (194 mg, 70%) as a white solid. The crude product was used directly for the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]([NH:16]C(=O)OC(C)(C)C)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C@H:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Agent: N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S,Z)-tert-butyl 1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylcarbamate (10 mg, 0.030 mmol) in DCM (0.2 mL) at rt was added TFA (0.2 mL). The clear solution was stirred at rt for 40 min. The reaction mixture was concentrated and dried in vacuum to give (S,Z)-3-amino-1-benzyl-3,4,7,8-tetrahydroazocin-2(1H)-one (7.0 mg, 0.030 mmol, 100% yield) as an oil. Anal. Calcd. for C14H18N2O m/z 230.3. found: 231.1 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC([O:5][CH2:6][CH3:7])=O.O[C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:75]CC(O)=O>O1CCCC1>[C:6]([S:75][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)(=[O:5])[CH3:7]
Reactant: O=C(OCCN1CCN(C(=O)[C@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A solution of 0.73 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 2.1 g of (2R,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] and 1.1 g of triphenylphosphine in 14 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. A solution of 0.32 g of mercaptoacetic acid in 2 ml of tetrahydrofuran was then added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.2 g of (2R,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine as a colorless powder.