Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([O:21][Si:31]([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32])[CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxycyclohexyl)propanoate (96.56 g, 0.32 mol) in CH2Cl2 (500 mL) was added imidazole (43.52 g, 0.64 mol), followed by TBSCl (72 g, 0.48 mol) at 0° C. After addition, the mixture was allowed to stir at rt overnight. The reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and evaporated to give (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propanoate (133 g, yield 100%). 1H NMR: (CDCl3, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.45 (s, 9H), 1.51 (m, 4H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H), 3.71 (d, 3H), 3.91 (m, 1H), 4.34 (m, 1H), 4.86 (m, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:41]=[CH:40][C:12]2[N:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=3)[C:14]([CH2:16][CH3:17])=[N:15][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:16]([C:14]1[N:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[C:12]2[CH:40]=[CH:41][C:9]([OH:8])=[CH:10][C:11]=2[N:15]=1)[CH3:17]
Reactant: CCc1nc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (step 5, 78 mg, 0.13 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF, 0.16 mL, 0.16 mmol) at 0° C. The mixture was stirred at 0° C. for 2.5 h, then concentrated. The residue was dissolved in water (30 mL) and extracted with dichloromethane (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 57 mg (92%) of the title compound as white amorphous: MS (ESI) m/z 479 (M+H)+; 1H-NMR (DMSO-d6) δ 7.76 (2H, d, J=7.6 Hz), 7.35-7.39 (6H, m), 6.96 (1H, s), 6.85 (1H, d, J=8.6 Hz), 6.65 (1H, d, J=8.6 Hz), 6.51 (1H, br.s), 3.17 (2H, br.s), 2.76 (2H, t, 6.6 Hz), 2.67 (2H, q, J=7.6 Hz), 2.34 (3H, s), 1.20 (3H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH:9][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])=[N:6][CH:7]=1
Reactant: NCc1cc(O)c(N)cn1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-2-aminomethyl-pyridin-4-ol (60 mg, 0.19 mmole as the dihydrobromide), 3 mL of N,N-dimethylformamide and triethylamine (101 uL, 0.72 mmole) were stirred for 15 mins, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (63 mg, 0.19 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in dimethylsulfoxide and purified by HPLC (acetonitrile-water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a brown solid, 5.5 mg, (5%); MS (ES+): m/z 437.0 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][C:12]=1[Br:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2csc(-c3ccc4c(c3)OCO4)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1sc(-c2ccc3c(c2)OCO3)nc1Cc1ccccc1
Reaction time: 8 h

Procedure:
367 mg of 4-benzyl-2-(3,4-methylenedioxyphenyl)thiazole was dissolved in 2 ml of N,N-dimethylformamide 244 mg of N-bromosuccinimide was added thereto under ice-cooling, followed by stirring overnight. Then, ethyl acetate was added to the reaction solution, followed by washing with water. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 3% ethyl acetate/hexane as an eluent for separation and purification, to give 377 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.[BH3-][C:18]#[N:19].[Na+]>C1C=CC=CC=1>[N:10]1[CH:9]=[CH:8][CH:14]=[CH:13][C:12]=1[CH2:16][NH:19][CH2:18][C:3]1[CH:2]=[CH:11][C:6]([CH2:7][NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][CH2:9][CH2:8][CH2:7]3)=[CH:5][CH:4]=1
Reactant: Nc1cccc2c1NCCC2
Reactant: C1CCOC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Product: c1ccc(CNCc2ccc(CNc3cccc4c3NCCC4)cc2)nc1

Procedure:
A stirred solution of 8-amino-1,2,3,4-tetrahydroquinoline (0.136 g, 0.92 mmol) and N-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine (0.370 g, 0.90 mmol) in benzene (20 mL) was heated to reflux under Dean-Stark conditions for 24 hours. The mixture was concentrated, dissolved in MeOH (10 mL) and THF (2 mL) and treated with NaBH3CN (0.094 g, 1.49 mmol) for 72 hours. The mixture was concentrated and partitioned between CH2Cl2 (20 mL) and a 1.0 M aqueous solution of NaOH (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by flash chromatography (24 g silica gel, 20:1 CH2Cl2-CH3OH) gave the desired product (0.137 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Reactant: BrC1c2ccccc2C1Br
Agent: BrC1c2ccccc2C1I
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21
Reaction time: 16 h

Procedure:
A mixture of 5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (ca. 37 mmol) of 1,2-dibromobenzocyclobutene (contaminated with a small amount of 2-bromo-1-iodobenzocyclobutene) and 100 ml of xylene is kept for 16 hours under reflux using a water separator. The mixture is cooled and the precipitate is isolated by filtration and washed with xylene. The yield is 5.82 g (71%); m.p. 253°-254° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2>C1COCC1.C(O)C.[Ni].O.[NH4+].[OH-]>[NH2:25][CH2:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.104 g, 0.3 mmol) in THF (1 mL) and ethanol (4 mL) was treated with a suspension of Raney nickel in water (1 mL) and aqueous NH4OH (0.5 mL). The mixture was stirred at ambient temperature for 12 h under hydrogen atmosphere (1 atm.). After this time GC-MS indicated that all the starting material was consumed. The reaction mixture was filtered and concentrated to afford the desired product. The material was used without purification.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[N:12]([O-])=O.[Na+].Cl.[Sn](Cl)[Cl:18]>>[CH:7]1[C:6]([NH:9][NH2:12])=[CH:5][CH:4]=[C:3]([S:1]([NH2:11])(=[O:10])=[O:2])[CH:8]=1.[ClH:18]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Product: NNc1ccc(S(N)(=O)=O)cc1
Reaction time: 4 h
Yield: 55 %

Procedure:
Compound 30c, 3-[1-{p-(Sulfonamido)phenyl}-5-p-tolyl-1H-pyrazol-3-yl]propanoic acid, was synthesized by the method depicted in FIG. 2. Briefly, 4′-methylacetophenone and succinnic hydride were reacted in the presence of lithium diisopropanolamine (LDA) and tetrahydrofuran (THE) for 1 hour at −78° C. to produce p-tolyl-4,6-dioxohexanoic acid as a white solid (66% yield). Also sulfanilamide has reacted with sodium nitrite (NaNO2) and concentrated hydrochloric acid at 0-4° C. for 30 minutes, after which tin(II) chloride (SnCl2) was added and the reaction allowed to continue for an additional 4 hours at 0° C. to produce 4-sulfonamidophenylhydrazine hydrochloride as a pale yellow solid (55% yield). The 4,6,dioxo-6-p-tolylhexanoic acid and the 4-sulfonamidophenylhydrazine hydrochloride were then complexed for 16 hours at room temperature in the presence of triethanolamine (TEA) in methanol to produce Compound 30c as a yellow solid (76% yield).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: NN
Reactant: COc1ccc2nc(Cl)c(OC)nc2c1
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(NN)c(OC)nc2c1
Temperature: 50 °C

Procedure:
A mixture consisting of 5 g. (0.022 mole) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g. (0.056 mole) of hydrazine hydrate (2.7 ml.) in 75 ml. of ethanol was heated at 50° C. overnight. Upon completion of this step, a further 1.0 ml. of hydrazine hydrate was added to the mixture and the resulting mixture was heated at 50° C. for a period of six hours. At this point, another 1.0 ml. of hydrazine hydrate was added and the final reaction mixture was heated at 50° C. overnight prior to being cooled to room temperature. The spent mixture was then filtered and the recovered precipitate washed with ethanol to ultimately afford 4.1 g. (85%) of pure 3,6-dimethoxy-2-hydrazinoquinoxaline, m.p. 128°-130° C. (decomp.).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cncnc1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 90 mg, 0.185 mmol), pyrimidin-5-ylboronic acid (22.9 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0092 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.26 min, m/z=448.1 [M+H]+, m/z=446.2 [M−H]−.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH:11]N1C2C=CC=CC=2N=N1>CC(C)=O>[C:9]1(=[O:11])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:6][CH2:7][CH2:8]1.[OH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][CH2:1]2
Reactant: c1ccc2c(c1)CCCC2
Reactant: On1nnc2ccccc21
Solvent: CC(C)=O
Product: O=C1CCCc2ccccc21
Product: Oc1cccc2c1CCCC2
Yield: 42 %
Yield: 90 %

Procedure:
212 mg (1.60 mmol) of 1,2,3,4-tetrahydronaphthalene in 1.1 ml of acetone were reacted analogously to Example 1 with 71 mg (0.53 mmol) of 1-hydroxy-1H-benzotriazole in 3 ml of acetone and 15 ml of an aqueous solution of 2 mg/ml laccase from Trametes versicolor. After a reaction time of 24 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 42% of 1-tetralone and 6% of 5-hydroxytetralin (approx. 90% yield of 1-tetralone based on conversion).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O.CCOCC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
1.7 g (3.99 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(p-methoxy-phenylmethyl)-dihydrofuran-2-(3H)-one in 43 ml of dimethoxyethane and 11 ml of water are hydrolysed with 16 ml of 1M lithium hydroxide solution. Stirring in ether yields the pure title compound: TLC Rf (F)=0.53; tRet (I)=14.2 min; FAB-MS (M+Na)+ =466.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanamine (5.834 g, 28.592 mmol) in pyridine were added methanesulfonyl chloride (4.2 mL, 54.325 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give N-(4-bromo-2-fluorobenzyl)methanesulfonamide (7.597 g, 93%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:27][C@H:28]2[O:30][CH2:29]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:30]1[CH2:29][C@H:28]1[CH2:27][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
1-Naphthol (1.0 g) was dissolved in DMF (8 ml) under nitrogen atmosphere and the solution was cooled to 0° C. 25 Cesium fluoride (2.1 g) was added thereto and the mixture was stirred for 1 hour. Then, (S)-glycidyl m-nitrobenzenesulfonate (1.80 g, 99.3% e.e.) was added thereto and the mixture was stirred for 24 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 6:1) to give 1.34 g of (S)-1-(2,3-epoxypropoxy)naphthalene (yield 96.5%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[N:11]1([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A solution of 1.5 g (0.01 mol) of chlorobenzoxazole in 20 ml of dichloromethane is added dropwise at 0° C. to a solution of 1 g (0.012 mol) of piperazine and 7 ml (0.05 mol) of triethylamine in 10 ml of dichloromethane and the mixture is stirred for one hour at this temperature. Then it is extracted with water. The organic phase is dried over sodium sulphate, the drying agent is filtered off and the filtrate is concentrated by evaporation. The residue is washed with acetone.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[C:15](O)(=O)[CH2:16][OH:17]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:15]([CH2:16][OH:17])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)CO
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(CO)nc2n(CC)c1=O
Yield: 59.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 5.0 g (25.2 mmol) of 5,6-diamino-1,3-diethyluracil [J. Am. Chem. Soc., 75, 114 (1953)] and 8.4 g (111 mmol) of glycolic acid. The resulting crude crystals were recrystallized from methanol to give 3.56 g (yield 60%) of Compound d as white needles.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.ClCCl.CN(C=O)C.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].[CH3:32][C:33]([CH3:54])([CH3:53])[CH2:34][CH2:35][NH:36][C:37](=[O:52])[C@H:38]([CH3:51])[CH2:39][C@H:40]([OH:50])[C@@H:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.ClCCl>[CH2:42]([C@H:41]([NH:49][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=1)[C@@H:40]([OH:50])[CH2:39][C@H:38]([C:37](=[O:52])[NH:36][CH2:35][CH2:34][C:33]([CH3:32])([CH3:53])[CH3:54])[CH3:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (100 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with dichloromethane (0.5 ml) followed by a solution of 1-hydroxybenzotriazole (22 mg, 0.14 mmol) in 4:1 dichloromethane/DMF (0.5 ml). 3-Methanesulfonyl benzoic acid (28 mg, 0.14 mmol) in DMF (0.5 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (30 mg, 0.094 mmol) in dichloromethane (0.5 ml) were then added and the mixture was stirred gently overnight at room temperature. It was then diluted with dichloromethane (0.5 ml) and treated with methylisocyanate polystyrene (100 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (100 mg @ 3.20 mmol/g; ex. Novabiochem), and the mixture was stirred gently for a further 1.5 h. It was then filtered and the spent resins were washed with DMF (1 ml) and dichloromethane (1 ml). The combined filtrates were evaporated to dryness and the residue was triturated with diethyl ether/hexane to afford the title compound (E1) as a white solid (23 mg, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:19]=[C:18](OC)[CH:17]=[CH:16][C:14]=1[NH2:15].CN(C)[CH:24]=[O:25].C[N:28](C=O)C>>[NH2:28][C:18]1[C:17]([O:25][CH3:24])=[CH:16][C:14]([N:15]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:13]([O:12][CH3:11])[CH:19]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1cc(N=Nc2ccc([N+](=O)[O-])cc2)c(OC)cc1N
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
A diazonium salt synthesized from 4-nitroaniline using the procedure of example 1 (1.4 g, 5.9 mmol) was added portionwise to a solution of 2,4-dimethoxyaniline (0.97 g, 6.3 mmol) in dimethylformamide DMF) (20 ml). The resulting red mixture was stirred for 1.5 h, filtered, and the resulting solid recrystallized from ethyl acetate (EtOAc)/Hexanes to give 1.3 g (70.6%) of Compound 5.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][CH:9]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10][CH:11]([OH:17])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13].OS(O)(=O)=O>CCOCC.O>[C:1]([O:17][CH:11]([CH2:10][CH:9]([CH3:8])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(C)=CCCC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CC(C)CCC=C(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.21 h
Yield: 39.6 %

Procedure:
A flask containing 1.15 g of acetic anhydride was cooled to −10° C. with a salt-ice bath, and 3.1 g of 4 was added with magnetic stirring under an N2 atmosphere. After 10-15 min, 25 mL of concentrated H2SO4 was added. The reaction mixture was allowed to stir for an additional 10 min, after which it was diluted with 40 mL of ether and 10 mL of H2O. The mixture was extracted three times with 15 mL of saturated aqueous sodium bicarbonate and once with 10 mL of saturated aqueous NaCl. The ether layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to yield 1.40 g of a mixture of stereoisomers of the nitro acetate 5. 1H NMR δ (ppm) 5.4 (br m, CHOCOCH3), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 4.4 (m, CHNO2), 2.1 (s, CH3CO2), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.9 (d, CH2CH(CH3)CH2).