Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][N:13]([CH3:15])[CH3:14]>[Fe].C(O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cc(N)ccc1Cl
Yield: 54.6 %

Procedure:
Iron (1.36 g, 21.9 mmol) and concentrated hydrochloric acid (0.15 mL) was added to ethanol/water (20 mL/20 mL), followed by refluxing for 1 hour. The mixed reaction solution was added with 1-(2-chloro-5-nitrophenyl)-N,N-dimethylmethanamine (940 mg, 4.38 mmol) obtained in <Step 1> above, and refluxed for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (chloroform:methanol=30:1→15:1 (v/v)) to obtain the title compound (442 mg, 55%).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:28])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CCOP(=O)(CCCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
4,6-Dichloro-2,5-diformamidopyrimidine (0.35 g, 1.5 mmol), diethyl 4-(aminooxy)butylphosphonate (0.216 g, 0.93 mmol) and N,N-diisopropylethylamine (0.521 ml, 3 mmol) were dissolved in diglyme (15 ml) and stirred at 100° C. for 3 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (4×20 ml) and the combined chloroform solutions were evaporated to dryness. The residue was chromatographed on silica gel (eluted with chloroform-ethanol, 96:4) to yield the title compound (0.330 g, 81%). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.7 (6H, m, CH2CH2CH 2 P), 3.87 (2H, t, J=5Hz, OCH2), 3.98 (4H, m, (OCH2CH3)2) 8.14 (1H, s, 5-NHCHO), 8.31 (1H, s, 6-NHCHO), 9.24 (1H, br.s, 2-NHCHO), 9.41 (1H, br.s, D2O exchangeable, NHOCH2), 10.81 (2H, br.s, D2O exchangeable, NHCHO, NHCHO).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21][NH:20][CH2:19]2)[CH:13]=[C:14]([Cl:17])[C:15]=1[Cl:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][C:18]([C:12]3[CH:13]=[C:14]([Cl:17])[C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=3)([C:23]([F:24])([F:25])[F:26])[CH2:19]2)[N:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
2-Chloro-6-methylpyridine (1.6 g), 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-pyrrolidine (4.0 g), sodium t-butoxide (1.5 g), tris(dibenzylidenacetone)dipalladium (0)-chloroform adduct (0.2 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.25 g) were added to toluene (15 ml), and heated for 1 hour at 120° C. using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). Upon the completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the precipitate was filtered off through a short silica gel layer. The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine (3.4 g).
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:46])[CH:15]([C:20]1[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:52]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([F:35])[CH:31]=1)[CH2:27][O:26][C:24]1[CH:25]=[C:20]([C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:46])=[O:52])[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=2)[CH:23]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](C(=O)O)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (0.425 g, 0.67 mmol) in THF (10 mL) was added water (3.5 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (0.028 g, 0.67 mmol) and 30% H2O2 (304 mL, 2.68 mmol), drop-wise, maintaining the internal temperature below 5° C. The resulting cloudy solution was stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (1.79 mL, 2.68 mmol) and stirred at room temperature for 5 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×25 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (S)-2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (0.295 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]2[CH2:32][O:33][CH2:34][CH:28]2[CH2:27]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]5[CH2:32][O:33][CH2:34][CH:28]5[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Reactant: ClCCCN1CCC2COCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated to 80° C. and stirred overnight, then cooled to room temperature. To the resulted mixture was added 50 mL of CH2Cl2. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.56%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 453.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (3H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.02 (1H, s), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21](B1OB(C=C)OB(C=C)O1)=[CH2:22]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:21]=[CH2:22])[CH:11]=1)([O-:14])=[O:13]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
12.0 g (46.1 mmol) of methyl 2-bromo-4-nitrobenzoate were initially charged in 240 ml of 1,2-dimethoxyethane, 2.66 g (2.30 mmol) of tetrakis(triphenylphosphine)palladium were added, and the mixture was stirred for 20 min. Subsequently, a solution of 6.38 g (46.1 mmol) of potassium carbonate in 80 ml of water and 11.11 g (46.1 mmol) of 2,4,6-trivinylcyclotriboroxane were added. The reaction mixture was stirred at reflux temperature for 20 hours. After cooling, the mixture was added to water and extracted with ethyl acetate, the organic phases were dried with magnesium sulphate, and the solvent was distilled off under reduced pressure. The residue was chromatographed using silica gel with cyclohexane/ethyl acetate (ratio 6:1) as the eluent. 4.5 g (46% of theory) of methyl 4-nitro-2-vinylbenzoate were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine in a analogous manner to example 712. Product was isolated as a pink solid (0.122 g, 22%); Mp 58-62° C.; LCMS (m/e) 503 (M); 1H-NMR (DMSO, 400 MHz) δ 11.09 (s, 1H), 9.26 (s, 1H), 8.6-6.61 (d, 1H), 8.15 (s, 1H), 7.65-7.63 (d, 1H, J=7.83 Hz), 7.43-7.39 (t, 1H, J=7.58 Hz), 7.37 (s, 1H), 7.24-7.20 (t, 1H, J=7.83 Hz), 7.17 (s, 1H), 7.13 (s, 1H), 7.00-6.98 (d, 1H, J=7.83 Hz), 6.87 (s, 1H), 6.64 (s, 1H), 3.77 (s, 3H), 3.58 (s, 2H), 3.31 (s, 3H), 3.10-2.99 (q, 2H, J=7.33 Hz), 2.90 (m, 2H), 2.76 (m, 2H), 2.40-2.33 (q, 2H, J=7.08 Hz), 2.18 (s, 2H), 1.14-1.08 (t, 3H, J=6.79 Hz), 1.09-1.03 (t, 3H, J=7.07 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C[Sn](C)(C)[C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1.NC1C=NC(Br)=CN=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:2]2[CH:3]=[C:4]([C:9]3[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[N:19][CH:20]=1
Reactant: Cc1ccc(-c2nn(C)c(=O)o2)cc1Br
Reactant: C[Sn](C)(C)c1cnc(N)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1cnc(Br)cn1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nn(C)c(=O)o2)cc1-c1cnc(N)cn1
Temperature: 75 °C

Procedure:
To a solution of 5-(3-bromo-4-methylphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (500 mg, 1.76 mmol) and 5-(trimethyl stannyl)-pyrazine-2-amine (683 mg, 2.65 mmol, prepared from 2-amino-5-bromopyrazine by following the procedure described in Chem. Eur. J. 2000, 6, 4132) in THF (10 mL) was added Pd(PPh3)4 (100 mg, 0.088 mmol). The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was heated at 75° C. for 15 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography over silica gel using ethyl acetate-hexane mixture as eluent to afford 250 mg of the intermediate 15b as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.99 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.62 (s, 2H, D2O exchangeable), 3.36 (s, 3H), 2.35 (s, 3H); ESI-MS (m/z) 284 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)OC)cc3c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)O)cc3c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.2 %

Procedure:
To a solution of methyl 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoate (0.023 g, 0.65 mmol), as prepared in the preceding step, in methanol (3 mL) was added sodium hydroxide (0.15 g, 3.8 mmol) in H2O (0.5 mL) and the reaction was stirred for 6 hours at ambient temperature. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl, extracted with a mixture of ethyl acetate and butanol (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound as a solid (0.018 g, 82%). 1H-NMR (400 M Hz, CDCl3+CD3OD) δ 7.52 (t, J=7.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.14 (d, J=3.1 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.81 (dd, J=8.9, 2.4 Hz, 1H), 6.60 (d, J=7.3 Hz, 1H), 6.38 (d, J=8.6 Hz, 1H), 6.33 (d, J=3.2 Hz, 1H), 4.38 (t, J=7.0 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.89 (s, 3H), 2.77 (t, J=6.9 Hz, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C19H21N3O3 340.3 (M+H); Found: 340.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)=[CH:15]1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:28][C:25]2[S:26][CH:27]=[C:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:14][CH:15]=3)[N:24]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Yield: 66 %

Procedure:
Prepared from 3-nitrophenyl acetic acid (1 g, 5.52 mmol), N-(1-methanesulfonyl)-benzotriazole (1.5 eq, 1.6 g), 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine and triethylamine (3eq, 2.3 ml) in THF (20 mL) by microwave irradiation at 170° C. for 10 mins as described above. The reaction mixture was concentrated to dryness and CH3CN added. The desired final product was filtered and washed with ether to give clean 2-(3-nitrophenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1.4 g, 66% yield.)
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][NH:11][CH3:12]>CCO>[CH3:10][N:11]([CH3:12])[C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CNC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])N(C)C

Procedure:
In 50 ml of EtOH was dissolved 3.3 g of 1,1-bis(methylthio)-2-nitroethylene and 2.2 ml of a 40% aqueous solution of dimethylamine was added dropwise in 2 portions at 30-minute intervals under refluxing. After completion of dropwise addition, the mixture was further refluxed for 30 minutes. Then, the EtOH was distilled off and the residue was subjected to silica gel column chromatography using CHCl3 --MeOH (20:1) as an eluent. The procedure gave 1.0 g of 1-dimethylamino-1-methylthio-2-nitroethylene as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14].[H-].[Na+].[CH3:17]I>CN(C=O)C>[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH3:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1ccc2c(c1Br)CCCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1Br)CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
6-Bromo-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (100.0 mg, 1.998 mmol) was treated with NaH (18.9 mg, 0.472 mmol, 1.2 equiv) in DMF (3 mL) at 0° C. to room temperature for 30 min. To the mixture was added MeI (111.7 mg, 0.787 mmol, 2 equiv). The mixture was stirred at to room temperature for 1 h The mixture was quenched with water and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure and the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 87:13 to 50:50) to give 6-bromo-1,7-dimethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (88.5 mg, 83.9%).
Reaction SMILES: C(#N)C.Br.[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH:17][C:20](=[O:22])[CH3:21])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Yield: 120.1 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III), R1=ethyl] and 38.75 g of acetic anhydride. 38.03 g of triethylamine were dropwise added to the resulting suspension in about 10 minutes. The suspension was refluxed, obtaining complete dissolution at a temperature ranging from 70 to 75° C. After approx. 2 hours 30 minutes the solution was concentrated to dryness, and the residue was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O.C(C1C=CC=CC=1C(O)=O)=O.C([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH2:51])[CH:37]([OH:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])(C)(C)C>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C@@H:12]([CH2:16][CH3:17])[C:13]([NH:51][C@H:36]([C:37](=[O:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])[CH2:35][C:34]([OH:52])=[O:33])=[O:15]
Reactant: CC[C@@H](C(=O)O)n1ccc2ccccc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: O=Cc1ccccc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccccc2c1=O

Procedure:
This compound was prepared using (S)-2-(1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared from 2-formylbenzoic acid using procedures similar to those described in methods A-E) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The title compound was isolated by preparative HPLC. IR (solid) 2960.2, 1780.1, 1746.2, 1646.6, 1619.0, 1589.1, 1517.4, 1490.3, 1427.8, 1260.3, 1206.2, 1176.3, 1098.9, 938.4, 788.1, 748.3, 714.2, 692.5, 665.3 and 655.8 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 0.78-0.83 (3H, m), 1.89-1.96 (1H, m), 2.08-2.13 (1H, m), 2.50-2.78 (2H, m), 4.35-5.45 (4H, 3×m), 6.64-6.69 (1H, m), 7.74-7.73 (5H, m), 8.18-8.20 (1H, m), 8.81 & 8.90 (1H, d) ppm; 19F NMR (376 MHz, DMSO) (proton decoupled) δ −141.01, −141.03, −141.07, −141.09, −156.80, −156.82, −156.86, −156.88; MS ES (+) 509.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([OH:11])[CH2:6]1.O.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1
Reactant: COC(=O)C[C@H]1CCC[C@@H](O)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
rac-cis-(3-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) (Example 5, step 1) was dissolved in 2 ml dichloromethane and tetrapropylammonium perruthenate [TPAP] (102 mg, 0.29 mmol) and 4-methylmorpholine oxide monohydrate (590 mg, 4.35 mmol) were added. The reaction mixture was stirred for 16 hours at room temperature, filtered over dicalite and evaporated to dryness. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→50:50 gradient). The desired compound was obtained as a light yellow liquid (240 mg, 48%).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl>C1COCC1>[F:2][C:3]1[CH:11]=[C:10]([NH2:1])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Aq ammonia (6.0 mL, 32% in water) is added to a mixture of 2,4-difluoro-5-nitro-benzoic acid (6.0 g, 30 mmol) in THF (80 mL) and it is stirred over the weekend at rt. The mixture is acidified with 6N aq HCl-solution and the precipitate is filtered, washed with water and dried at 55° C. and directly used in the next step.
Reaction SMILES: C([O:3][C:4](=[O:24])[C@H:5]([CH3:23])[NH:6][C:7](=[O:22])[C@H:8]([CH3:21])[NH:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)C.[Li+].[OH-]>O1CCOCC1.O>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:24])=[O:3])[CH3:23])=[O:22])[CH3:21])=[O:20])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reaction time: 3 h

Procedure:
The title compound was prepared by dissolving 1.98 g (0.006 mols) of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 below) in 60 mL dioxane and 15 mL of H2O and adding LiOH (0.25 g, 0.006 mol) that has been dissolved in 15 mL of H2O. After stirring for 3 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 ml), and the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 1.7 g (90%). C,4H,6F2N2O4 requires C, 53.50 H, 5.13 N, 8.91. Anal found C, 53.30 H, 5.26 N, 8.98.