Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2.C(#N)C.Cl[C:18]1[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=1.Cl>C(OCC)(=O)C.[Fe]>[C:1]12([C:12]3[CH:11]=[C:10]([O:13][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=4)[CH:9]=[CH:8][C:7]=3[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Oc1ccc2c(c1)C1(CCC1)OC2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1cnc(Oc2ccc3c(c2)C2(CCC2)OC3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a solution of spiro[1H-isobenzofuran-3,1′-cyclobutane]-5-ol (Intermediate 24, 50 mg, 0.28 mmol) in dry acetonitrile (4 mL) dipotassium carbonate (58.8 mg, 0.43 mmol) and then 2-chloro-5-nitro-pyrimidine (43.0 mg, 0.27 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was diluted with ethyl acetate (20 ml) and washed with an aqueous saturated solution of ammonium chloride (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (5 mL)/water (1 mL). Iron (95.0 mg, 1.7 mmol) and an aqueous 6M solution of hydrogen chloride (0.05 ml, 0.3 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (10 ml) and extracted with ethyl acetate (2×15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 60:40 to 0:100 as eluent affording the title compound (24 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:32])[C:26]=1[N+:33]([O-:35])=[O:34]>CC(O)C>[Cl:31][C:30]1[C:25]([N:12]2[CH2:11][CH2:10][N:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([NH2:32])=[N:28][CH:29]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(CCc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
1-Phenethylpiperazine (0.100 g, 0.52 mmol, 1.1 eq) was suspended in iPrOH (1 mL). DIPEA (0.13 mL, 0.79 mmol, 1.5 eq) was added followed by 4,5-dichloro-3-nitropyridin-2-amine (0.099 g, 0.48 mmol, 1 eq). The mixture was heated and stirred at 65° C. overnight. The mixture was cooled to room temperature and filtered. The bright yellow solid was washed with iPrOH (3×2 mL), Et2O (2×2 mL) and dried to give the title compound as a bright yellow solid (0.112 g, 64%); 1H-NMR (500 MHz, DMSO-d6): δ 2.53-2.63 (m, 6H), 2.71-2.78 (m, 2H), 3.06 (m, 4H, piperazine N(CH2)2), 6.95 (s, 2H, NH2), 7.15-7.21 (m, 1H), 7.22-7.31 (m, 4H), 8.06 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.31 min—362/364 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:38]([O:37][C:35](=[O:36])[C:27]1[CH:28]=[C:29]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])[CH:4]=2)[CH:30]=[CH:31][C:26]=1[Cl:25])[CH3:39]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c2)ccc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 189, step 5) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=544.2 [M+H+].
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:8]([Cl:11])(Cl)Cl>C(#N)C>[CH:1]([N:4]([P:8]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[Cl:11])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
A 5-liter, 3-neck, round-bottom flask was equipped with a Fredrich's condenser, a ground glass stirrer bearing, a silicon rubber septum, and placed under dry argon. Two liters (1,600 grams, 15.9 mmols, 7.0 eq) of anhydrous diisopropyl amine was added to the flask. The diisopropyl amine was diluted by the addition of two liters of anhydrous acetonitrile. The solution was mixed with a mechanical stirrer attached to a glass stir rod and Teflon blade. An ice/water bath was placed under the 5-liter flask, and the amine solution allowed to cool for 30 min. Phosphorus trichloride (313 grams, 2.3 mmols, 1.0 eq) was dissolved in 1 liter of anhydrous acetonitrile in a separate dry 1-liter flask. The mechanical stirrer was set to vigorous stirring and the phosphorus trichloride solution added slowly to the stirring flask by cannula. Once the addition was complete, the ice/water bath was removed, and the reaction was allowed to warm to room temperature. The reaction was stirred overnight and the extent of the reaction determined by 31P NMR of an aliquot of the reaction mixture using an external lock. Complete conversion of the starting material, phosphorus trichloride (δ 201 ppm), into the product at δ 134 ppm, demonstrated completion of the desired reaction. The reaction mixture was filtered to remove the bulk of the diisopropylamine hydrochloride, which had precipitated. The precipitate was washed with anhydrous ether and the filtrates evaporated into a 2-liter round-bottom flask. The resulting evaporated product was a semi-crystalline solid, which was suspended in 1 liter of anhydrous hexanes. The flask was heated on a mantel, to allow the hexanes to boil. The hot liquid was filtered through a Schlenk filter-funnel to remove residual amine hydrochloride. This resulting clear yellow liquid was evaporated to one half the original volume and placed in a freezer to allow the product to recrystallize. The recrystallized product was isolated by filtration and dried in a vacuum desiccator, yielding 447 grams (74% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([O:10][P:9]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(F)cc1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethyl phosphite (8.86 mL, 68.8 mmol) at ambient temperature, followed by the addition of triethylamine (9.6 mL, 68.8 mmol). The resulting solution was degassed with nitrogen followed by the addition of tetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol). The resulting mixture was heated at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The crude product was purified by vacuum distillation (ca. 98° C., 0.6 Torr) to yield 8.956 g of 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.88-7.80 (m, 2H); 7.20-7.14 (m 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z): M+1)+ found, 233.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:27]C(Br)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Br:27])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)Br
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(Cc1cc(F)cc2cc(Br)oc12)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of 0.50 gm (1.71 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 17 mL tetrahydrofuran at −78° C. were added 2.4 mL (3.84 mMol) n-butyllithium (1.6 M in hexane) dropwise. The resulting mixture was stirred for 1.5 hour and then 0.16 mL (1.86 mMol) dibromoethane were added. After stirring for an additional hour the reaction mixture was poured into a mixture of 25 mL saturated aqueous sodium bicarbonate and 50 mL diethyl ether. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride. All aqueous phases were combined and extracted with 50 mL diethyl ether. All organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 15% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.53 gm (89%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CCO
Product: CCNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 77 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 20.8 g of ethylamine are added as 33% solution in water. The reaction mixture is refluxed for 2 hours and is then evaporated to dryness. The precipitate obtained is taken up in 100 ml of water. After 1 hour's stirring, the mixture is filtered on sintered glass. The precipitate is recrystallized from 25 ml of acetonitrile. 8.10 g of 2-amino-4-ethylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [C:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12](N=CC3C=CC=CC=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(COC2C=CC=CC=2)C=CC=CC=1.[CH2:37]([N:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[C:51]1([N:44]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:45]2[CH:46]=[CH:47][C:48]([N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:49][CH:50]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: C(=Nc1ccc(N=Cc2ccccc2)cc1)c1ccccc1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(COc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: c1ccc(CN(c2ccccc2)c2ccc(N(Cc3ccccc3)c3ccccc3)cc2)cc1

Procedure:
N,N'-Bis(phenylmethylene)benzene-1,4-diamine (1.42 g, 0.005 mol) and phenylmethoxybenzene (1.84 g, 0.010 mol) were heated in Na/DMF (1 g: 50 mL) at 100° C. for 1 hr. Similar workup as for the preparation of benzyldiphenylamine and chromatography on silica using petroleum ether/chloroform 4:1 as eluent gave 0.35 g (16%) mp 149-51° C. from ethyl acetate. 1H NMR (200 MHz, CDCl3)δ (assignment): 4.96 (s,4H, PhCH2N--), 6.80-6.97 (m, 6H, aromatic), 7.05 (s, 4H, (PhCH2 (Ph)N)2C6H4), 7.16-7.33 (m, 14H, aromatic). MS [m/e (70 eV, % of base peak)] (PhCH2 (Ph)N)2C6H4 440 (M+., 25.4), 349 (M+. --C7H7., 24.5), 91 (C7H7+, 100). HRMS (m/z) for C32H28N2 (M+.) calcd. 440.225, found 440.227.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C1(S)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2noc(=O)[nH]2)C1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c([C@@H]2CCNC2)no1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
Crude (R)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (872 mg, 3.41 mmol), CH2Cl2 (5 mL) and thiophenol (0.7 mL, 6.8 mmol) were combined and diluted with TFA (5 mL). After 24 h, the reaction was concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The layers were separated and the CH2Cl2 layer was extracted with water. The combined aqueous layers were concentrated in vacuo. Reverse phase HPLC purification yielded 482 mg of (R)-3-pyrrolidin-3-yl-4H-1,2,4-oxadiazol-5-one as a tan oil (˜50% pure) that was used without further purification.
Reaction SMILES: [H-].[Na+].CO.[C:5]1([C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29]OS(OC)(=O)=O>C1COCC1>[C:23]1([C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([O:22][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COS(=O)(=O)OC
Reactant: C=CCCCCCCCCC(O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCCCCCC(OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1.2 g of sodium hydride and 0.1 mL of methanol in 50 mL of THF was added a solution of 10 g of 1,1-diphenyl-10-undecen-1-ol in 20 mL of THF over 2 hrs. The mixture was stirred at room temperature for 4 hrs, then 3.5 mL of dimethylsulfate was added. The mixture was stirred for an additional 75 hrs, then 2 mL of methanol was added to quench any excess sodium hydride. The solvent was distilled in vacuo, the residue taken up in ether, and the solution washed with 10% by wt of hydrochloric acid, water, and saturated sodium hydrogen carbonate. The solution was then dried with sodium sulfate and concentrated in vacuo to give 10.6 g of 11,11-diphenyl-11-methoxyundec-1-ene which is characterized by:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ncccc1OCCCCl
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccnc1C
Temperature: 100 °C
Yield: 61 %

Procedure:
The 3-chloro-1-(2-methyl(3-pyridyloxy))propane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCI solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and the mixture was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated to give 1.19 g (61.0%) of an oil.
Reaction SMILES: C(NC(C)C)(C)C.CN(C)CCN(C)C.C([Li])CCC.C(N(CC)[C:24](=[O:39])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])C>C1COCC1>[N:27]1[C:26]2[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][C:24](=[O:39])[C:25]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCN(CC)C(=O)c1cccnc1Nc1ccccc1C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1Cc2ccccc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.61 mL, 53.89 mmol) and tetramethylethylenediamine (8.13 mL, 53.89 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 34.2 mL, 54.77 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min., then 0° C. for 10 min. This solution was transferred into a solution of N,N-diethyl-2-(o-tolylamino)nicotinamide in THF (100 mL) at 0° C. The resulting solution was stirred overnight and quenched by adding saturated ammonium chloride solution (20 mL). The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the pure desired product, 6,11-dihydro-5H-benzo[f]pyrido[2,3-b]azepin-5-one (2.2 g) as a yellow solid. 400 MHz 1H NMR (DMSO-d6) δ: 10.20 (s, 1H), 8.47-8.53 (m, 1H), 8.16-8.13 (m, 1H), 7.41-7.39 (m, 1H), 7.32-7.25 (m, 2H), 7.19-7.15 (m, 1H), 6.98-6.95 (m, 1H), 3.72 (s, 2H); LCMS (M+H)=211.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.C(O[C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27]([OH:29])=[O:28])=O)C1C=CC=CC=1.COC(=O)CN1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.Cl[C:64]1([N+:70]([O-:72])=[O:71])[CH:69]=[CH:68][CH:67]=[N:66]C1>>[C:34]([O:33][C:31]([NH:30][CH:26]([CH2:25][NH:24][C:22]1[C:64]([N+:70]([O-:72])=[O:71])=[CH:69][CH:68]=[CH:67][N:66]=1)[C:27]([OH:29])=[O:28])=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: O=[N+]([O-])C1(Cl)C=CC=NC1
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1[N+](=O)[O-])C(=O)O

Procedure:
(2S) 2-tert-Butoxycarbonylamino-3-(3-nitropyridin-2-ylamino)propionic acid was prepared by a similar method as (2S) 2-tert-butoxycarbonylamino-3-(2-nitrophenyl-amino)propionic acid in Step A of the synthesis of 600a/103, except that 3-chloro-3-nitro pyridine was used instead of 2-fluoronitrobenzene, to give 4.05 g (64%) of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].C([Li])CCC.CCCCCC.[CH:22](=[O:24])[CH3:23].Cl>C1COCC1>[NH2:4][C:3]1[C:5]([Br:10])=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[CH:22]([OH:24])[CH3:23]
Reactant: CC=O
Reactant: Nc1c(Br)cc(Cl)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc(Br)c1N
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
At −78° C. under nitrogen 1.8 M phenyl magnesium chloride solution in THF (3.06 ml, 5.5 mmol) were added dropwise to 2,6-dibromo-4-chloroaniline (1.426 g, 5.0 mmol) in THF (25 ml). The clear solution was warmed to −20° C. and stirred at this temperature for 5 minutes. The clear yellow solution was cooled to −78° C. and 1.6 M n-butyllithium solution in hexane (6.25 ml, 10 mmol) was added dropwise. The reaction was warmed to −10° C. and again cooled to −78° C. at which temperature acetaldehyde (440 mg, 10 mmol) dissolved in THF (5 ml) was added. After stirring for 10 minutes at −78° C. 1N aqueous hydrogen chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was extracted twice with diethyl ether, dried over sodium sulfate, filtered and the solvent was evaporated to yield the product as a mixture of the corresponding amine, imine and aminal. The crude product was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N+:55]([O-])=O)[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>CCOC(C)=O.CO.[Ni]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:36][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:55])[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc([N+](=O)[O-])cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(N)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-6-nitro-quinoxaline (3) (0.159 g, 0.198 mmol) was dissolved in a mixture of EtOAc (3 mL) and MeOH (3 mL). The solution was heated to 60° C. and Raney Nickel (0.25 mL, 50% slurry in water) and hydrazine (0.5 mL, anhydrous) were added. Bubbling was observed. The mixture continued to stir for 15 minutes at 60° C. TLC (Rf: 0.05 compared to Rf: 0.3 for compound 245 in 1:1 hexanes/EtOAc) indicated complete reduction at this point. The mixture was passed through a plug of silica gel and concentrated to give a white powder. The solid was dissolved in EtOAc (30 mL), washed with water (2×20 mL) and brine (2×20 mL) via extraction, dried over MgSO4 and concentrated to give the desired product (246) as a white powder (0.135 g, 0.175 mmol, 88.3% yield). LC-MS (ESI): (exact mass: 771.46) m/e=772.6 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:12][O:13][CH:14]([O:20]C)[CH2:15][C:16](OC)=O>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][CH:16]=[C:15]2[C:14]([O:13][CH3:12])=[O:20]
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c2ccc(OC)cc12
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 110.2 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride (200 mg) and methyl 3,3-dimethoxypropionate (194 mg) were added to acetic acid (8.0 ml) and stirred for 4.5 hours at 70° C. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:5→1:3) to give methyl 5-methoxy-1H-indole-3-carboxylate (259 mg, Y.:97%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=O)[CH3:11].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCOc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.13 g), 3-ethoxybenzoic acid (997 mg) and phosphorus oxychloride (24 ml) was stirred at 120° C. for 2 hours and poured onto ice. The mixture was neutralized with 8 N sodium hydroxide, stirred for 20 minutes and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water, dried over MgSO4. The solvent was distilled off under reduced pressure and the resulting crystals were collected by filtration to obtain 6-bromo-2-(3-ethoxyphenyl)-1H-imidazo[4,5-b]pyridine (978 mg, 51%).