Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(C)[C@H]1CCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC[C@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.30 (m, 1H) 2.33 (d, J=2.27 Hz, 4H) 2.76-2.93 (m, 6H) 3.52-3.78 (m, 3H) 3.83-4.00 (m, 2H) 7.63 (d, J=7.83 Hz, 1H) 7.74 (t, J=7.58 Hz, 1H) 8.21 (d, J=7.58 Hz, 3H) 8.67 (s, 1H).). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+:41]>O1CCOCC1>[NH2:41][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])=[O:11]
Reactant: [NH4+]
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid in dioxane were added Py (1 eq.), Boc2O (1.3 eq) and ammonium bicarbonate (1.26 eq.). The reaction mixture was stirred at RT for 72 hours and then the solvent was evaporated under reduced pressure. The resulting crude was diluted with EtOAc and washed with H2O, 1 N HCl and brine. The organic phase was dried (Na2SO4) and concentrated under reduced pressure to yield a white powder which was as such in the next step. MS (ES) C15H28N2O4 requires: 300, found: 301 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C)C=O>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:17][CH2:16]1
Reactant: Nc1ccccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)NCCO2
Temperature: 130 °C
Reaction time: 7.5 h

Procedure:
To a solution of 2-aminophenol (8.01 g) in N,N-dimethylformamide (70 ml), potassium carbonate (51.0 g) and 1,2-dibromoethane (9.5 ml) were added and stirred at 130° C. for 7.5 hours and then at room temperature for 3 days. After addition of additional 1,2-dibromoethane (9.5 ml), the reaction mixture was stirred at 130° C. for 6 hours. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 5:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzoxazine (3.77 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C(=O)C)=[CH:6][C:5]=1[OH:14].OS(C(F)(F)F)(=O)=O.[C:24](Cl)(=[O:26])[CH3:25].CCOC(C)=O>O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:24](=[O:26])[CH3:25])[C:7]([OH:10])=[CH:6][C:5]=1[OH:14]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C

Procedure:
The toluene solution from Step 1 was cooled in an ice bath under N2 and triflic acid (9.44 L) added slowly over 3 h. On stirring a fine white solid was formed which dissolved on warming to RT over 20 h and then stirring at RT for 37 h to give a yellow solution. To the solution was added acetyl chloride (726 mL) and the solution stirred at RT for a further 1 h. This solution was cannulated into a stirred cooled (0° C.) solution of EtOAc (217.8 L) and NaOAc.3H2O (14.52 Kg) dissolved in water (145 L). The organic phase was washed with saturated brine (twice, 72.6 L), and was evaporated to 5.5 Kg. Toluene:Isopropanol (2:3) was added and the crystalline solid removed by filtration and dried to give 12.6 Kg (61% over 2 steps), mp 124-126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([C:12]2[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19](=O)[NH2:20])[CH:8]=2)[O:3]1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([C:12]2[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]#[N:20])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2ccc[nH]c2=O)c2cc(C(N)=O)ccc2O1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(c2ccc[nH]c2=O)c2cc(C#N)ccc2O1
Reaction time: 0.75 h

Procedure:
A mixture of 2.98 g of 2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-6-carbamoylchroman,2 ml of POCl3 and 200 ml of 1,2-dichloroethane is boiled for 45 min. Cooling and customary working up gives 2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-6-cyanochroman, m.p. 174°-175.5°.
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>>[OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1)=[O:5]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To (R)-2-hydroxy-2-phenylacetic acid (200 mg), methyl 2-(3-(4-aminophenyl) isoxazole-5-carboxamido)-3-methylbutanoate (417 mg), in N,N′-Dimethyl formamide (5 ml), DCC (406 mg) and HOBT (177 mg) were added and stirred at RT for 16 hours. The reaction mixture was filtered and concentrated to obtain brown oil which was purified by column chromatography (silica gel, EtOAc—CHCl3) to obtain pale brown solid which was crystallized from DCM-Petroleum ether to yield 235 mg (39%) of the title compound as off white solid. MS (ES+): m/z 452 (M+1); 1H NMR (DMSO-d6; 300 MHz): δ 10.19 (s, 1H), 9.2 (d, 1H), 7.88 (d, 4H), 7.69 (s, 1H), 7.54 (m, 2H), 7.39-7.27 (m, 3H), 6.51 (d, 1H), 5.13 (d, 1H), 4.3 (m, 1H), 3.67 (s, 3H), 2.24 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH2:29])=[CH:7][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([OH:20])([CH3:21])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH:29][C:41]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:7][C:6]=2[N:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)(C)O
Reactant: CC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.17 h

Procedure:
1-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol dihydrochloride (prepared as described in Part A of Example 654, 0.466 g, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.0 mmol) were combined. The mixture was stirred for 10 minutes. Isopropyl isocyanate (0.097 mL, 1.00 mmol) was added and the reaction was stirred for 16 hours. Saturated aqueous sodium carbonate (˜8 mL) was added and the layers were separated. The organic layer was concentrated and purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The fractions containing product were combined and concentrated. Trituration of the product in dichloromethane, followed by filtration provided 0.319 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea as an off-white powder.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 50.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (140 mg, 0.234 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (154 mg, 0.469 mmol), Pd(PPh3)2Cl2 (3.22 mg, 0.011 mmol), sodium carbonate (75 mg, 0.702 mmol), Toluene/ethanol (3/5 ml) to afford 80 mg (51% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.63 (s, 1H), 8.14-8.12 (d, 2H), 8.04 (s, 1H), 7.73-7.64 (m, 3H), 7.49-7.46 (m, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (d, 1H), 7.01-6.95 (m, 2H), 6.86-6.83 (d, 1H), 5.31 (s, 2H), 4.84-4.83 (m, 1H), 4.03 (s, 3H), 2.63-2.61 (d, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H). MS: m/z=674.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]([SH:15])[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]3[S:15][CH2:29][CH2:30][N:13]3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
5-(3-Nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (298 mg, 1.0 mmol) was dissolved in dry DMF (12.5 mL) under nitrogen atmosphere. Solid potassium carbonate (690 mg, 5 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.086 mL, 1 mmol, 1 eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (60 mL) and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. 280 mg of 6-(3-nitro-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole were obtained as an off-white solid (87%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2/[CH:23]=[N:24]/[OH:25])=[C:5]([CH3:26])[O:4][N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:24][OH:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1/C=N/O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
10% of the crude (E)-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (1.2 mg, 0.003 mmol) from step (e) was dissolved in CH2Cl2 (4 mL) and BBr3 (1 M solution in DCM, 0.4 mL, 0.37 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and DCM were added and the phases were separated. The organic phase was purified on preparative HPLC to give E4 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (0.58 mg, 3% over three steps). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 341.16 (M+II), 339.25 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.84 s 1H, 7.14 m 2H, 6.85 m 2H; (missing m 2H under H2O); 2.18 s 3H, 1.85 s 3H, 1.75 m 2H, 0.99 t (7.6 Hz) 3H.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([SH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(N(C)C)=O.C[O-].[Na+]>CO>[CH2:10]([S:24][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCS
Reactant: O=C(O)c1ccc(Br)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCCCCCCCCCCCCCSc1ccc(C(=O)O)s1

Procedure:
A mixture of 18.6 g (0.090 mole) of 5-bromo-2-thiophenecarboxylic acid, 25.0 g (0.109 mole) of 1-tetradecanethiol and 500 ml of dried dimethyl acetamide is stirred at room temperature after which 10.8 g (0.200 mole) of sodium methoxide is added. The mixture is heated and the methanol formed is allowed to distill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10% aqueous hydrochloric acid, filtered, and the precipitate washed with water and dried. The solid obtained is crystallized from the methanol then recrystallized from hexane to give 5-(tetradecylthio)-2 -thiophene carboxylic acid, M.P. 106°-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:43]([NH:50][CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][NH2:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][NH:53][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NCC(NCc1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(NCc1ccccc1)c1ccccc1
Yield: 11.5 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (70 mg, 0.13 mmol) and N1-benzyl-1-phenyl-1,2-ethandiamine dihydrochloride (45 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (11 mg) as a diastereomeric mixture. 1H-NMR (400 MHz, CD3OD) d 7.50 (1H), 7.45-7.03 (17H), 4.40 (m, 1H), 4.25 (m, 1H), 4.06 (m, 1H), 3.80 (s, 2H), 3.03 (m, 1H), 1.33 (s, 9H); HRMS m/z 738.3281 (calc. of monoisotopic mass for C41H46N4O9 gives 738.3265).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then benzoyl chloride (4.15 ml,) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 7.70 g of brown liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 244, 213, 196, 105(base), 77.
Reaction SMILES: [N:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:11]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C@H:12]([CH3:14])[NH:8][C:7]1[CH:9]=[CH:10][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Reactant: CC(=O)C(=O)OCC(C)C
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(N=[N+]=[N-])cc1

Procedure:
Following General Procedure AA above and using 4-azidoaniline (Aldrich) dan iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf 0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:7]=1[CH:8]1[O:4][CH2:1][CH2:2][O:3]1
Reactant: O=Cc1ccc(F)c(F)c1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C2OCCO2)c(F)c1F
Reaction time: 24 h

Procedure:
Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: BrBr
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAC was added Br2 (0.5 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as a white solid. 1H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1)[CH:2]=C.[O:17]=[O+][O-]>ClCCl>[O:17]=[CH:2][CH2:1][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCC2)O1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-9-(2-propenyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), as added and the colorless solution is allowed to warm to room temperature. Fash chromatography provides after concentration in vacuo 2.5 g of pure (±)-cis-9-(2-oxo-ethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[Cl:16]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Triethylamine (0.52 mL, 3.75 mmol) was added to a mixture of 4-bromo-3-chlorophenol (156 mg, 0.75 mmol), phenyl boronic acid (187 mg, 1.53 mmol), Cu(OAc)2 (208 mg, 1.15 mmol), molecular sieves (4 Å), and dichloromethane (7.5 mL). The mixture was stirred at room temperature overnight, and then additional phenyl boronic acid (186, 1.53 mmol) was added. The reaction was stirred at rt for an additional 7 h and filtered through Celite with dichloromethane. The filtrate was concentrated and purified by silica gel chromatography (100% hexanes) to give 1-bromo-2-chloro-4-phenoxybenzene (90 mg) as a clear liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, 1H), 7.42-7.47 (m, 2H), 7.27 (d, 1H), 7.23 (t, 1H), 7.11 (d, 2H), 6.92 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)CCCc1ccccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Initially charge 705 mg (3.37 mmol) of 4-(2-nitrophenyl)butanoic acid in 7 ml of methanol, cool to 0° C. and add 0.26 ml (3.54 mmol) of thionyl chloride dropwise. Warm the mixture slowly to RT and stir overnight. To complete the reaction, add an approx. 20% excess of thionyl chloride and stir the mixture at RT for a further 5 h. After concentration under reduced pressure, stir the residue in a little methanol and filter off the resulting solid. 700 mg (95.5% of theory) of the target product are obtained as a white solid.