Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
138 g. (1 mole) of 4-hydroxybenzoic acid was dissolved in 1 liter of 95% ethanol and 500 ml. of 2N sodium hydroxide solution. To this solution was added 346 ml. (3 mole) of benzyl chloride and the mixture was boiled under reflux. 1 liter of 5N sodium hydroxide was added dropwise over a period of 2 hours and the mixture heated a further hour with stirring. The solvent was distilled to half its volume, 2 liters of water added, the warm aqueous solution acidified with hydrochloric acid and the precipitated product recrystallised from 80% ethanol, m.p. 188°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:29][C:26]3[S:25][C:24]([Cl:23])=[CH:28][CH:27]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: ClCc1ccc(Cl)s1
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 100.3 %

Procedure:
This compound was prepared following the procedure described in example 7, part E, starting with 2 g (6.6 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 0.94 ml (8 mmol) of 2-chloro-5-(chloromethyl)thiophen. After standard work-up and purification, 2.86 g of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester were obtained.
Reaction SMILES: [CH:1]([O:4][SiH:5]([O:10][CH:11]([CH3:13])[CH3:12])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH:14]([Si:16]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])[O:17][CH:18]([CH3:20])[CH3:19])=[CH2:15]>C1(C)C(C)=CC=CC=1>[CH:7]([O:6][Si:5]([O:4][CH:1]([CH3:3])[CH3:2])([O:10][CH:11]([CH3:13])[CH3:12])[CH:15]=[CH:14][Si:16]([O:17][CH:18]([CH3:20])[CH3:19])([O:21][CH:22]([CH3:24])[CH3:23])[O:25][CH:26]([CH3:28])[CH3:27])([CH3:9])[CH3:8]
Reactant: CC(C)O[SiH](OC(C)C)OC(C)C
Reactant: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1C
Product: CC(C)O[Si](C=C[Si](OC(C)C)(OC(C)C)OC(C)C)(OC(C)C)OC(C)C
Temperature: 225 °C

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.012 mol) triisopropoxysilane, 5.7 g (0.024 mol) vinyltriisopropoxysilane, 1.0 xylene and 200 ppm Ru3CO12 (20 mg). The reaction was heated for 4 hours at 225° C. in a fluidized sand bath. A single product, 1,2-bis(triisopropoxysilyl)ethylene was formed.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([C@H:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
To a solution of a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (755 mg) and 4-dimethylaminopyridine (440 mg) in dichloromethane (6 ml) was added dropwise a solution of p-nitrobenzyl chloroformate (660 mg) in dichloromethane (4 ml) during three minutes period at 0° C. After 1.5 hours, the solution was concentrated, taken up into ethyl acetate (40 ml), and washed with dilute hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and evaporated to leave an oil. Chromatography on silica gel (50 g) eluting with 2-10% ethyl acetate in dichloromethane to give methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate (974 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH:10]([CH3:13])[CH2:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)#[N:2].Cl.C(=O)([O-])[O-:20].[Na+].[Na+]>O>[C:1]([CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH:10]([CH3:13])[CH2:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)(=[O:20])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC1Cc2ccccc2CN(CCC#N)C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1Cc2ccccc2CN(CCC(N)=O)C1=O
Yield: 66 %

Procedure:
A solution of 2.1 g. (0.0092 moles) of 2-(2-cyanoethyl)-4-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 5 ml. of 35% hydrochloric acid is heated for 30 minutes at 40° C., while stirring. The reaction mixture is poured into 30 ml. of water and the pH adjusted to 9 by the addition of sodium carbonate, with vigorous stirring. The precipitate formed is washed with water, dried and then recrystallized from diisopropyl ether. 1.5 g. (66% of theory) of 2-(2-carbamoylethyl)-4-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is obtained. M.P. 168°-169° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:5]2
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Yield: 88 %

Procedure:
5-Hydroxy-1H-2-indolecarboxylic acid (328 mg) was dissolved in ethanol (10 ml) to prepare a solution. Concentrated sulfuric acid was added to the solution, and the mixture was heated under reflux for 3 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydrogencarbonate solution was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane to give ethyl 5-hydroxy-1H-2-indolecarboxylate (336 mg, yield 88%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[CH:9][CH:8]=1.[N+:25]([O-])([OH:27])=[O:26]>>[F:6][C:7]1[C:8]([N+:25]([O-:27])=[O:26])=[CH:9][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:18]=2)=[CH:11][CH:12]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To 2.5 ml of concentrated sulfuric acid was added 0.34 g of 3-(4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-4) at 5° C. Furthermore, 0.13 ml of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.337 g (yield, 85%) of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13; m.p., 134.4° C.).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=[C:4]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:3]=1.CC(N(C)C)=O.[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:28]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][CH3:31])[C:22]=1[C:4]1[N:3]=[C:2]([N:45]2[CH2:46][CH2:47][C:42]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:43][CH2:44]2)[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=1)[CH3:29]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC3(CC2)OCCO3)n1
Temperature: 85 °C

Procedure:
To a vial containing [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (1.0 mL of a 0.2M DMA solution, 0.2 mmol) is added 1,4-dioxa-8-azaspiro(4,5)decane (1.0 ml of a 1.0M DMA solution, 5.0 eq.) and the resulting solution is vortex heated at 85° C. for 12 h. Once the reaction has cooled to room temperature, EtOAc (1.0 mL) and sat NaHCO3 (1.0 mL) is added and the organic layer is plated directly onto a SiO2 preparatory chromatography plate and the product is eluted using hexanes:Et2O 1:1, which affords the title compound as a colorless oil. [mass expected (540.74); mass found (540.43)].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[Br-].[CH:30]1([Zn+])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1COCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:7][N:6]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: [Zn+]C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C4CCCCC4)cn3)c2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (146 mg, 0.30 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (12 mg, 0.015 mmol) under dry nitrogen add with stirring a solution of 0.5 M cyclohexylzinc bromide in THF (3.0 mL, 1.5 mmol). Degas, purge with dry nitrogen, and stir overnight at 60° C. Cool to ambient temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (46 mg, 32%). MS (APCI+) m/z: 487 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (APCI+) m/z: 387 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH:33]=[CH:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)Cl>[Br:20][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:35]([O:37][CH3:38])=[O:36])[CH2:34][CH:33]=[CH:32][CH2:31]2)=[CH:26][CH:25]=1
Reactant: BrBr
Reactant: COC(=O)C1(c2ccc(CO)cc2)CC=CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(CBr)cc2)CC=CC1

Procedure:
To a solution of triphenylphosphine (8.03 g, 30.6 mmol) in 100 ml CH2Cl2 at 0° C. was added dropwise bromine (1.45 ml, 28.1 mmol). After 15 minutes at 0° C. a white precipitate formed and a solution of the product of Step 3, above, (5.93 g, 25.5 mmol) in 30 ml CH2Cl2 was added dropwise. After 1 hour the solvent was removed in vacuo and the residue was taken up in ether to precipitate the triphenylphosphine oxide formed in the reaction. After filtration, evaporation and SGC (5% EtOAc-hexanes) the title compound (5 g) was obtained as a colorless oil which crystallized on standing.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([CH3:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:24]=[C:25]([CH3:34])[C:26]([OH:32])=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:28]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(C)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.8 %

Procedure:
Boron trifluoride dimethyl sulfide (1.48 mL, 13.7 mmol) was added at 4° C. to a stirred solution of methyl-N-[3,5-dichloro-4-(5-isopropyl-4-methoxy-3-methylphenoxy)benzoyl]glycine (155 mg, 0.352 mmol) and dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 24 hours and then treated with ice-water (30 mL), extracted with ethyl acetate and concentrated. The residue was purified on column (MPLC, silica gel, chloroform/methanol/acetic acid, gradient elution from 1/0/0 to 95/5/0.5) to give 110 mg (76%) of N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-5-methylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 410.
Reaction SMILES: BrC1=C(CCCC)C(=O)O/C/1=C\Br.C([C:18]1[C:19](=[O:26])[O:20][C:21](=[C:23]([Br:25])[Br:24])[CH:22]=1)CCC>>[Br:24][C:23]([Br:25])=[C:21]1[O:20][C:19](=[O:26])[CH:18]=[CH:22]1
Reactant: CCCCC1=CC(=C(Br)Br)OC1=O
Agent: CCCCC1=C(Br)/C(=C/Br)OC1=O
Product: O=C1C=CC(=C(Br)Br)O1

Procedure:
The furanones to be used in accordance with the present invention may be obtained from natural sources or chemically synthesized. For example, (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone and 3-butyl-5-(dibromomethylene)-2-(5H)-furanone may be extracted and purified from seaweed (e.g., the marine algae Delisea pulchra) as previously described (see, e.g., de Nys et al. Tetrahedron 1993; 49:11213-11220). Alternatively, (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone, 3-butyl-5-(dibromomethylene)-2-(5H)-furanone, 5-(bromomethylene)-2-(5H)-furanone, 4-bromo-5-(bromomethylene)-2(5H)-furanone, and/or 5-(dibromomethylene)-2(5H)-furanone may be chemically synthesized as previously described (see, e.g.: Beechan and Sims. Tetrahedron Letters 1979; 19:1649-1652; Manny et al. Tetrahedron. 1997; 53:15813-15826; and Ren, Sims and Wood. Let. Appl. Microbiol. 2002; 34-293-299).
Reaction SMILES: C1([Se][Cl:8])C=CC=CC=1.[CH2:9]([C:12]1([NH2:27])[CH2:16][CH2:15][C@@H:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1)[CH:10]=[CH2:11]>C(#N)C>[Cl:8][CH:10]1[CH2:9][C:12]2([CH2:16][CH2:15][C@@H:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)[NH:27][CH2:11]1
Reactant: C=CCC1(N)CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: Cl[Se]c1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H]1CCC2(CC(Cl)CN2)C1
Temperature: 80 °C

Procedure:
To phenylselenyl chloride (0.199 g, 1.041 mmol) was added (1R)-benzyl 3-allyl-3-aminocyclopentanecarboxylate (example 2, step A, 0.090 g, 0.347 mmol) dissolved in acetonitrile (2 mL). The contents were heated at 80° C. for 18 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. To the residue was added methanol (5 mL). The solid that separates was filtered and washed with methanol (2 mL). To the filtrate was added 4.0N hydrogen chloride in dioxane (1 mL) and the contents concentrated. Ethyl acetate was added and the resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added and a solid separates out The liquid was carefully pipetted out into a HPLC vial and subjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated. The residue was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield (7R)-benzyl 3-chloro-1-azaspiro[4.4]nonane-7-carboxylate (0.051 g, 0.174 mmol, 50.0% yield) as an oil. It was used as such for the subsequent step. MS (ESI) m/z 294.14 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28](O)=[O:29])[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([Br:27])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:76][N:77]([CH3:84])[CH:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([Br:27])[CH:21]=3)[C:28]([N:81]3[CH2:82][CH2:83][CH:78]([N:77]([CH3:84])[CH3:76])[CH2:79][CH2:80]3)=[O:29])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)[C@@H](Cc1cc(Br)cc(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)[C@@H](Cc2cc(Br)cc(Br)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 150 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 90 mg (0.28 mmol) TBTU, 95 μL (0.55 mmol) ethyldiisopropylamine and 38 mg (0.28 mmol) HOBt in 6 mL DMF was stirred for 90 min at RT. Then 42 mg (0.33 mmol) 4-dimethylamino-piperidine were added and the reaction mixture was stirred for 16 h at RT. The reaction solution was combined with water, the organic phase was evaporated down and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 95:5:0.5).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([N:18]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([O:31]C(C4C=CC=CC=4)=O)[CH2:27][CH2:26]3)C(=O)C(F)(F)F)[CH:10]=2)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[F:46][C:47]1[CH:48]=[C:49]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[NH2:60].O[Li].O>C(Cl)Cl.N1C=CC=CC=1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[NH:60][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[NH:18][C@H:25]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)[C@H]3CC[C@@H](OC(=O)c4ccccc4)CC3)c2)CC1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N[C@H]3CC[C@@H](O)CC3)c2)CC1
Reaction time: 2 h

Procedure:
4-(4-methylpiperazin-1-yl)-2-[{cis-4-[(phenylcarbonyl)oxy]cyclohexyl}(trifluoroacetyl)amino]benzoic acid hydrochloride (1.03 gr, 1.94 mmol) and oxalyl chloride (3.88 mmol) were stirred in DCM dry (20 mL) and a few drops of dry DMF at 0° C., temperature was allowed to reach room temperature in 2 hours. Volatiles were evaporated and the residue dissolved in dry pyridine (25 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (387 mg, 1.49 mmol) in dry pyridine (6 mL) was added to the cooled reaction mixture. Temperature was allowed to reach room temperature overnight. Reaction was quenched with NaHCO3 sat. sol and extracted with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/AcOEt/EtOH=100/10/15). The so obtained derivative, was dissolved in MeOH (200 mL) and water (20 mL) and treated at 60° C. with LiOH hydrate (160 mg, 3.8 mmol) for 4 hours. MeOH was evaporated and the resulting aqueous phase was extracted with EtOAc. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/EtOH/NH3 5N in MeOH=100/10/2) affording 233 mg of title compound.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.O1CCOCC1.[ClH:35]>CO>[ClH:35].[ClH:35].[NH2:8][CH:9]([CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1cccnc1)COc1noc2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(COc1cccnc1)COc1noc2ccccc12

Procedure:
To a solution of 0.30 g of 3-[2-tert-butoxycarbonylamino-3-(3-pyridyloxy)propoxy]-1,2-benzoisoxazole in 5 ml of methanol is added 1 ml of a dioxane solution (3.2N) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for two hours, after which the crystals precipitated are collected by filtration, to obtain 0.24 g of colorless, crystalline 3-[2-amino-3-(3-pyridyloxy)propoxy]-1,2-benzoisoxazole dihydrochloride having a melting point of 216.8°-218.9° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:23])=[C:4]([CH:8]=[C:9]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([F:22])(=[O:21])=[O:20])[CH:14]=2)[CH:10]=1)[CH:5]=[N:6]O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])(=O)C.[Na+]>O>[C:24]([O:23][C:3]1[C:4]([C:5]#[N:6])=[CH:8][C:9]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([F:22])(=[O:21])=[O:20])[CH:14]=2)=[CH:10][C:2]=1[Cl:1])(=[O:26])[CH3:25]
Reactant: O=S(=O)(F)c1cccc(N=Nc2cc(Cl)c(O)c(C=NO)c2)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1c(Cl)cc(N=Nc2cccc(S(=O)(=O)F)c2)cc1C#N
Temperature: 95 °C

Procedure:
3-Chloro-5-(3-fluorosulfonylphenylazo)-2-hydroxybenzaldehyde oxime (22.5 g, 0.063 mol) was added to 150 ml acetic anhydride and heated to 95° C. Sodium acetate (3.0 g) was added. After 21/2 hours, the reaction mixture was poured into 750 ml water and stirred at room temperature until anhydride fully hydrolysed. The resulting precipitate was filtered off. The solids which became gummy on standing were dissolved in 75 ml chloroform and poured onto a silica gel column. Elution with 10% hexane in chloroform gave the desired dye as the first component. Removal of the solvents under reduced pressure gave an oil which hardened on standing but did not crystallize. Yield: 16.8 g (70%).