Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH2:16].O>C(OC(O)C)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:16][CH2:15][CH:14]([OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1c(Br)cnc2ccccc12
Reactant: NCC(O)c1ccccc1
Agent: CCOC(C)O
Solvent: O
Product: OC(CNc1c(Br)cnc2ccccc12)c1ccccc1

Procedure:
A solution of 4 g of 3-bromo-4-chloro-quinoline and 6 g of 2-hydroxy-2-phenyl-ethylamine was heated at 150° C. for 3 hours in 10 ml of ethoxyethanol. The mixture was cooled and poured into 150 ml of water. The product was extracted with two 50 ml portions of ether. The ether layer was dried over sodium sulfate, the solvent was evaporated and the residue was recrystallized from isopropanol. The yield was 3.0 g, mp 131°-132° C.
Reaction SMILES: [Na+].[Na+].[CH:3]([C:5]1[O:9][C:8]([S:10]([O-:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[S:14]([O-:17])(=[O:16])=[O:15])=O.[CH:18]([NH:21][OH:22])([CH3:20])[CH3:19].[Na][Na]>>[CH:18]([N+:21]([O-:22])=[CH:3][C:5]1[O:9][C:8]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[S:14]([OH:17])(=[O:16])=[O:15])([CH3:20])[CH3:19]
Reactant: O=Cc1oc(S(=O)(=O)[O-])cc1S(=O)(=O)[O-]
Reactant: CC(C)NO
Agent: [Na+]
Agent: [Na][Na]
Product: CC(C)[N+]([O-])=Cc1oc(S(=O)(=O)O)cc1S(=O)(=O)O

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2,4-disulfonic acid disodium salt and N-isopropylhydroxylamine, the title compound could be prepared as the disodium salt.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCc1ccc(CN)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(CCC(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenz-aldehyde and methyl 3-[4-(aminomethyl)phenyl]propanoate (purification by flash chromatography on SiO2, EtOAc/c-Hex 20/80) as a yellow oil (53%). 1H NMR (CDCl3) δ: 7.28 (d, J=8.3 Hz, 2H), 7.23-7.13 (m, 4H), 7.08 (d, J=7.9 Hz, 2H), 3.70 (s, 2H), 3.66 (s, 2H), 3.59 (s, 3H), 2.86 (t, J=8.3 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.56-1.46 (m, 2H), 1.43-1.31 (m, 2H), 0.86-0.76 (m, 3H). M+ (ESI): 420.4. HPLC, Rt: 4.5 min (purity: 99.5%).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Oc2ccccc2)c1
Yield: 99 %

Procedure:
To a solution of (3-(phenyloxy)phenyl)methanol (10 g, 49.4 mmol) in chloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and the mixture was heated under reflux overnight. The reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1-(chloromethyl)-3-(phenyloxy)benzene (10.7 g, 98%).
Reaction SMILES: CO[O:3][P:4]([O:9][CH2:10][CH:11]([OH:34])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15])([O:6]OC)=[O:5].C[Si](Br)(C)C>C(#N)C.ClCCl>[OH:34][CH:11]([CH2:10][O:9][P:4]([OH:5])([OH:6])=[O:3])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15]
Reactant: COOP(=O)(OCC(O)COC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)COP(=O)(O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
To a solution of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-2-hydroxy-propyl ester (60 mg, 0.4 mmol) in 1.5 mL of acetonitrile and 1.5 mL of dichloromethane was added 52 μl (0.40 mmoL) of TMSBr dropwise. The reaction mixture was stirred for 6 h at room temperature and concentrated. The residue was quenched with 0.05 mL of water followed by 1.5 mL of EtOAc. The resultant mixture was centrifuged and the solvent was decanted. The precipitate was washed twice with ethyl acetate and dried to afford 120 mg (62%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-phosphonooxy-propyl ester as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H, NH-1′), 7.84 (dd, J=2.4, 8.0 Hz, 1H, H-4), 7.79 (dd, J=2.2, 6.8 Hz, 1H, H-7), 7.64 (s, 1H, H-vinyl), 7.16–7.21 (m, 2H, H-5, 6), 6.11 (s, br, 1H, H-4′), 4.40 (dd, J=4.0, 10.8 Hz, 1H), 4.32 (dd, J=5.8, 11.2 Hz, 1H), 4.00–4.05 (m, 1H) 3.90–3.93 (m, 2H), 2.37 (s, 3H, CH3), 2.33 (s, 3H, CH3). 31P NMR (162 MHz, d6-DMSO) δ 0.16.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[CH:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:8]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH2:22]([O:20][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=2)[CH:6]=1)[CH3:23]
Reactant: OCc1cc(O)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(CO)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
3-(Hydroxymethyl)-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenol from Step 1 (460 mg, 1.61 mmol), in acetone (10 mL), was treated with 1-iodoethane (0.143 mL, 1.77 mmol), potassium carbonate (279 mg, 2.02 mmol) and 18-crown-6 (85 mg, 0.323 mmol). The mixture was heated to reflux for 16 h, cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30%, EtOAc:heptane) to afford the title compound (357 mg, 70% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:34])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CCCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
3-(4-Propylphenyl)propanol (s3) (11.0 g) and triphenylphosphine (24.3 g) were dissolved in methylene chloride (200 ml). Carbon tetrabromide (24.5 g) in methylene chloride (100 ml) solution was slowly added dropwise to the solution, and the mixture was stirred at room temperature for another 3 hours. The reaction mixture was treated with a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a residue, pale yellow solids. The residue was purified by column chromatography with heptane as an eluent and silica gel as a stationary phase powder to give 3-(4-propylphenyl)bromopropane (s4) (14.5 g). The yield based on the compound (s3) was 97.4%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:25].[OH-].[NH4+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)([C:22]([NH2:23])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC2(C#N)CCN(Cc3ccccc3)CC2)c1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl-4-cyano-4-(3-methylphenylamino)-piperidine (7.6 g) and 90% sulfuric acid (53 mL) was heated at 70° C. until all the solid dissolved (˜1 h). The resultant mixture was stirred at the temp. for 30 min., and poured into a mixture of ice (80 g) and concentrated ammonium hydroxide (75 g). The solution was basified with ammonium hydroxide, and extracted with chloroform. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To 5-aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine from step 92b (0.262 g, 0.80 mmol) were added CH2Cl2 (10 mL), triethylamine (0.1619 g, 1.60 mmol) and benzoyl chloride (0.1349 g, 1.0 mmol). The mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 9/1) to afford a light brown foam (0.267 g, 77%). MS (CI/NH3) m/z 432 (M+H+), 449 (M+NH4+). 1H NMR (CDCl3, 300 MHz): 1.57 (s, 9H), 2.25-2.37 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 4.11 (dd, J=2.7, 9.80 Hz, 1H), 4.31-4.39 (m, 1H), 4.49-4.55 (m, 1H), 4.68 (d, J=8.5 Hz, 2H), 6.75 (m, 1H), 7.42-7.56 (m, 4H), 7.79-7.82 (m, 2H), 8.03 (d, J=3.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12]C(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 3.75 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(benzyloxy)benzene, 5.0 g of 10% aqueous potassium hydroxide solution and 50 ml of methanol. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The concentrate was poured into water, and extracted twice with 150 m of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.56 g of 3-(2,6dichloro-4-(benzyloxy)phenoxy)-1-propyl alcohol (90% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:21])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (44 ml), ethyl-p-aminobenzoate (60 g), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-carbethoxy aniline (XI). XI had a m.p. of 87° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[C:7]1(C)[CH:12]=[CH:11]C=[CH:9][CH:8]=1.C(C1C=CC=CC=1)C>C1(C)C(C)=CC=CC=1>[CH2:5]1[C:6]2[C:9](=[CH:8][CH:7]=[CH:12][CH:11]=2)[CH2:2][C:1](=[O:3])[O:4]1
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Solvent: CCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1Cc2ccccc2CO1

Procedure:
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene and ethylbenzene. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85° C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=1.[H-].[Na+].[CH2:18]([O:20][C:21](Cl)=O)[CH3:19]>CN(C)C=O>[CH2:18]([O:20][CH2:21][N:3]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:7][CH3:8])[N:6]=[C:2]1[CH3:1])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CCc1nc(C)[nH]c1Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1c(C)nc(CC)c1Sc1ccccc1
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
To a solution of 500 mg of 4-ethyl-2-methyl-5-phenylthioimidazole 2 (2.3 mmol ) obtained in Example 1 (2) in 5 ml of dry dimethylformamide is added 140 mg of 60% oil suspension of sodium hydride (3.5 mmol) under ice cooling. Five minutes later, 330 mg of ethoxycarbonyl chloride (3.5 mmol) is added to the mixture, which is stirred for 15 minutes. The reaction mixture is poured onto ice water and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and the filtrate is concentrated. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (2:1) to give 410 mg of the desired product I-2 as an oil. Yield, 65%.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].O.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=O)=[CH:21][CH:20]=1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=[N:6][OH:7])=[CH:21][CH:20]=1
Reactant: O=CCc1ccc(COc2ccccn2)cc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=CCc1ccc(COc2ccccn2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of hydroxylamine sulfate (19.7 g) and water (250 mL) was added an aqueous solution of 1N sodium hydroxide (240 mL) at 0° C, which was stirred at the same temperature for 15 minutes. Then, at the same temperature, to the reaction mixture was added a mixture of (4-(pyridin-2-yloxymethyl)-phenyl)-acetaldehyde described in Preparation Example 2-1-3 (27.3 g) and methanol (250 mL) dropwise, which was stirred overnight at room temperature. The precipitated solids were filtered to obtain the title compound (20.3 g) as a mixture of E isomer and Z isomer.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([OH:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COC(=O)c1cccc(Br)c1C
Agent: Cl[Ru]Cl
Agent: [K+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c(O)ccc(Br)c1C
Temperature: 85 °C
Yield: 75.4 %

Procedure:
A solution of methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.40 g, 10.5 mmol) in trifluoroacetic acid (50 mL) and trifluoroacetic anhydride (20 mL) in a sealed tube was treated with potassium persulfate (3.12 g, 11.5 mmol) and dichloro(p-cymene)ruthenium(II) dimer (0.170 g, 0.278 mmol). The reaction mixture was heated at 85° C. overnight. The volatiles were removed under vacuum and the resulting residue was taken up in dichloromethane and water. The aqueous phase was brought to pH˜5 with K3PO4 (sat. aq.). The layers were separated and the organic layer purified by column chromatography (0-30% ethyl acetate/heptane) to give methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94 g, 75%) as a clear oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([OH:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+]([O-])=O)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[CH2:50]([NH-:52])[CH3:51]>CO.C(O)(=O)C.[Pd].O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([OH:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:29])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[C:4]([O-:7])(=[O:5])[CH3:3].[C:4]([O-:7])(=[O:5])[CH3:3].[CH2:50]([NH-:52])[CH3:51]
Reactant: COC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: CC[NH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)[O-]
Product: COC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 256 %

Procedure:
2.16 g (3.0 millimoles) of Z-Asp(OMe)-Leu-Arg(NO2)-Pro-ethylamide are dissolved in a mixture of 24 ml of methanol and 24 ml of acetic acid, thereafter 900 mg of 10% palladium-on-charcoal catalyst suspended in 24 ml of water are added under stirring and hydrogen gas is bubbled through the reaction mixture for 8 hours. Then the catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether and dried. Thus 1.73 g (87.3%) of title product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:18][C:12]1[O:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)co1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.82 g (3.27 mmol) of the compound from Example 9A are provided in 21 ml of acetic acid, 0.17 ml (3.27 mmol) of bromine are added and the mixture is stirred at 60° C. overnight. A saturated aqueous sodium carbonate solution is added carefully, and the mixture is extracted with ethyl acetate. The organic phase is washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 40:1). 1.05 g (91% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.11 g (0.73 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.21 g (68%) as a white solid; mp=121-123° C.; MS (+) ESI m/z=414 (M+H)+.
Reaction SMILES: Cl.Cl.[C:3](=[NH:11])([O:9][CH3:10])[CH2:4][C:5](=[NH:8])[O:6][CH3:7].C(N(C(C)C)C(C)C)C.[F:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=O>ClCCl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([O:9][CH3:10])[N:11]=[C:23]([CH:22]([F:21])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1
Reactant: COC(=N)CC(=N)OC
Reactant: O=C(Cl)C(F)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC)nc(C(F)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
Dimethyl malonimidate dihydrochloride (11.0 g) was suspended in dichloromethane (100 ml) at -40° C. Ethyl diisopropylamine (38.9 ml) was added dropwise over 15 minutes at -40° C., followed by 2-fluoro-2-phenylacetyl chloride (11.0 g) in dichloromethane (15 ml) over 10 minutes at -40° C. The reaction mixture was allowed to warm to room temperature and stand overnight. It was then diluted further with dichloromethane, washed with ammonium chloride solution, then with water, and was dried over magnesium sulfate. The dichloromethane solution was evaporated to dryness to give 13.9 g of the desired product.
Reaction SMILES: C[C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21](C#N)=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH:31]1([Mg]Br)CC1>[Cu]I>[CH:29]1([C:30]([C:21]2[CH:24]=[CH:25][C:18]([C:15]3[CH:16]=[CH:17][C:11]4[O:10][C:9]([CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C@H:2]5[CH3:31])=[CH:13][C:12]=4[CH:14]=3)=[CH:19][CH:20]=2)=[O:26])[CH2:27][CH2:28]1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Agent: [Cu]I
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C(=O)C4CC4)cc3)ccc2o1
Temperature: 60 °C
Yield: 44 %

Procedure:
The product from Example 1D (330 mg, 1.0 mmol) was dissolved into tetrahydrofuran (1 mL), treated with ˜0.7 M cyclopropylmagnesium bromide in tetrahydrofuran (2 mL, ˜1.4 mmol) and copper (I) iodide (a few milligrams), and heated at 45 ° C. for one day and at 60° C. for two days. The reaction was brought to room temperature, quenched with 0.4 M aqueous hydrochloric acid (5 mL), and extracted with EtOAc. The organic phase was washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (40 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min.] to provide the title compound as a powder (44% yield). MS (ESI APCI) m/z 374 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.06-1.21 (m, 7 H), 1.38-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94-2.08 (m, 1 H), 2.23-2.34 (m, 1 H), 2.40-2.59 (m, 2 H), 2.83-3.15 (m, 3 H), 3.19-3.34 (m, 2 H), 6.62 (s, 1 H), 7.51 (d, 1 H), 7.56 (dd, 1 H), 7.76-7.85 (m, 3 H), 8.12 (d, 2 H).