Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(O[Pd]OC(=O)C)(=O)C.CO.C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][C:14]=2[F:16])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Fc1ccc(-c2ccc(Br)cn2)c(F)c1
Temperature: 40 °C
Yield: 84 %

Procedure:
One 1.0 L round bottom flask was charged with 2,5-dibromopyridine (10.45 g, 44.1 mmol); (2,4-difluorophenyl) boronic acid (7.66 g, 48.5 mmol); potassium carbonate (12.19 g, 88 mmole); diacetoxypalladium (0.495 g, 2.206 mmol); triphenylphosphine (1.157 g, 4.41 mmol); and acetonitrile (348 ml) and MeOH (174 ml). The reaction mixture was heated to 40° C. for 40 hours. The reaction mixture was diluted with deionized water and extracted with ethyl acetate. The organic portion was combined and subjected to column chromatography (SiO2 gel, 10% EtOAc in heptane) to yield the desired compound, 5-bromo-2-(2,4-difluorophenyl)pyridine (10 g; 84%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([NH:15]C(OC(C)(C)C)=O)=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([CH:34]([CH3:36])[CH3:35])[CH:10]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([CH:34]([CH3:36])[CH3:35])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Sc2cc(N)c(N)cc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Toluene-4-thiosulfonic acid S-(4,5-bis-tert-butoxycarbonylamino-2-isopropyl-phenyl)ester (prepared in Example UU-1; 8.88 g, 16.6 mmol) was dissolved in CH2Cl2 (25 mL), and HCl gas was bubbled through the solution for 15 minutes. The reaction mixture was stirred at room temperature for 90 minutes. The solvents were evaporated, and the residue was dissolved in MeOH (10 mL) and treated with pH 7.5 buffer. The precipitate that formed was filtered and dried. MS(APCI): 337 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:11][CH2:10][CH:9]([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:12][CH:9]1[O:8][C:6]2[N:7]=[C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1COc2c(nc(-c3cnc(N)nc3)nc2N2CCOCC2)O1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-7-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (99 mg, 0.36 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (97 mg, 0.44 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol) and sodium carbonate (1.2 mL, 1.20 mmol, 1M aqueous solution) in acetonitrile (1.2 mL) was degassed then heated at 140° C. for 25 minutes using microwave irradiation. The reaction mixture was filtered, flushing with ethyl acetate. The filtrate phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM) then triturated with diethyl ether affording 103 as a white solid (12 mg, 11%). LCMS: RT=3.06 min, [M+H]+=331. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.01 (2H, s), 4.57-4.47 (1H, m), 4.36 (1H, dd, J=11.41, 2.34 Hz), 3.82 (1H, dd, J=11.43, 7.60 Hz), 3.77-3.61 (8H, m), 1.34 (3H, d, J=6.44 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:3]=1
Reactant: COC(Cc1cc(Br)ccc1[N+](=O)[O-])OC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(Cc1cc(Br)ccc1N)OC
Temperature: 25 °C
Yield: 47.5 %

Procedure:
Compound 66 (75 mg, 0.259 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask fitted with a magnetic stir bar and condenser. Sodium dithionite (158.8 mg, 0.776 mmol) and sodium bicarbonate (130.6 mg, 1.554 mmol) are added to the flask and mixture heated to reflux for 24 hours. After cooling to room temperature, the reaction was quenched by the addition of H2O (10 mL) and the ethanol removed under reduced pressure. The resulting aqueous layer was transferred to a separatory funnel and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (methanol:CH2Cl2, 2:98) to yield a brown oil, 67 (32 mg, 47.5%). 1H NMR (CDCl3) δ 2.83 (d, 2H, J=5.3 Hz), 3.38 (s, 6H), 4.48 (t, 1H, J=5.3 Hz), 6.61 (d, 1H, J=8.2 Hz), 7.13 (d, 1H, J=2.2 Hz), 7.15-7.17 (m, 1H); ESI-MS (m/z, %): 198/200 (M+−2MeO, 100%).
Reaction SMILES: [Li]CCCC.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Si:14]([O:21][C@@H:22]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:23](OCC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@@H:22]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:23]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: CCOC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(N)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
n-BuLi (3.40 mL, 1.6 M in hexanes, 5.44 mmol) was added slowly to a stirred solution of 2-amino-5-picoline (616 mg, 5.70 mmol) in anhydrous THF (8 mL). The reaction mixture was kept at ambient temperature for 10 minutes before a solution of ethyl (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(dimethylamino)butanoate (Step 2) (1.50 g, 5.18 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc) to give the title compound (320 mg), 1H NMR (300 MHz, CDCl3) δ 8.89 (br s, 1H), 8.12 (m, 2H), 7.51 (dd, 1H), 4.32 (t, 1H), 2.47 (m, 1H), 2.31 (m, 4H), 2.21 (s, 6H), 1.97 (m, 2H), 0.98 (s, 9H), 0.15 (d, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Asn-OtBu (38 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.11-12.80 (br.s, 1 H), 8.94 (s, 1 H), 7.99 (s, 1 H), 7.28 (m, 7 H), 7.18 (m, 3 H), 7.03 (m, 1 H), 6.96 (m, 2 H), 6.87 (m, 5 H), 4.50 (m, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.55 (m, 2 H), 2.44 (m, 2 H), 2.39 (s, 3 H), 2.11 (t, 2 H), 1.76 (m, 2 H); MS (APCI+) m/z 673 (M+H)+.
Reaction SMILES: C([O-])(=[O:3])C.[Zn+2:5].C([O-])(=[O:8])C.[CH3:10][C:11]([CH2:13][C:14]([CH3:16])=[O:15])=[O:12].[CH3:17][C:18]([CH2:20][C:21]([CH3:23])=[O:22])=[O:19].[CH3:24][C:25]([CH2:27][C:28]([CH3:30])=[O:29])=[O:26].[Cr:31].[O-2].[Zn+2]>>[O-2:3].[Zn+2:5].[O-2:8].[O-2:12].[Cr+4:31].[CH3:17][C:18]([CH2:20][C:21]([CH3:23])=[O:22])=[O:19].[CH3:24][C:25]([CH2:27][C:28]([CH3:30])=[O:29])=[O:26].[CH3:10][C:11]([CH2:13][C:14]([CH3:16])=[O:15])=[O:12].[Cr:31]
Reactant: CC(=O)[O-]
Agent: [Cr]
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC(=O)CC(C)=O
Product: [Cr+4]

Procedure:
The reactant mixture according to the present invention comprises zinc acetate, a quantity of chromium acetyl acetonate, and a solvent. The chromium acetyl acetonate is present in an amount effective to improve the chemical durability of the zinc oxide layer produced by spraying the reactant mixture against the hot surface of the glass. Zinc acetate pyrolyzes at the surface of the glass to form a layer of zinc oxide containing a small quantity of chromium dioxide commensurate with the amount of chromium acetyl acetonate contained in the reactant mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[OH:12])=[O:5])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1sc(C)nc1O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1sc(C)nc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (5.0 g, 26.74 mmol) in chloroform (80 mL) were added p-toluenesulfonyl chloride (5.61 g, 29.41 mmol) and triethylamine (4.84 mL, 34.76 mmol) at 0° C. The reaction mixture was allowed to warm to RT over 4 h, then diluted with DCM and H2O. The organic layer was isolated, washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a pale brown solid (8.1 g, 89%).
Reaction SMILES: CS[C:3]1[C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:11]=[C:12]([N:13]3[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]3)[C:7]=2[N:6]=[CH:5][N:4]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:3]1[C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:11]=[C:12]([N:13]3[CH2:14][CH2:15][S:16](=[O:19])[CH2:17][CH2:18]3)[C:7]=2[N:6]=[CH:5][N:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
1.9 gm (0.005 mol) of 8-methylthio-4-(1-oxido-thiomorpholino)-2-piperazino-pyrimido-[5,4-d]-pyrimidine (m.p.: 253°-255° C.) were heated with 25 ml of benzylamine for about one hour at 150° C. Subsequently, the excess amine was largely distilled off in vacuo, the residue was taken up in about 150 ml of water, and the solution was adjusted to pH 7 with dilute hydrochloric acid. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [I-].[CH:2]1([C:5]2[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[C:16]2[NH:25][C:19]3[CH:20]=[N+:21]([CH3:24])[CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH:2]1([C:5]2[C:6]([C:16]3[NH:25][C:19]4[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:18]=4[N:17]=3)=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:11])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nc3cc[n+](C)cc3[nH]2)c(C2CC2)cc1C
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2nc3c([nH]2)CN(C)CC3)c(C2CC2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of 2-(2-cyclopropyl-5-(methoxycarbonyl)-4-methylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-5-ium iodide (compound 87.3, 300 mg, 0.67 mmol) and NaBH4 (1.42 g, 37.5 mmol) in methanol (30 mL). The resulting mixture was stirred for 4 h at room temperature, then concentrated under reduced pressure. The residue was diluted with EtOAc (120 mL) and the mixture was washed with brine (2×40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc/MeOH (20/1) as the eluent to yield 170 mg (78%) the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(OCC2=C(c3ccccc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(OCC2=C(c3ccccc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)cc1
Yield: 75.9 %

Procedure:
To a solution of Example 7E (42 mg, 0.088 mmol) in a mixture of methanol/acetic acid (0.75 mL/0.75 mL), Zn powder (57 mg, 0.88 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high-pressure liquid chromatography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid to provide the title compound (30 mg, 76%)). 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.53 (m, 2H), 7.24-7.39 (m, 4H), 7.12-7.23 (m, 4H), 6.68-6.82 (m, 2H), 4.40-4.51 (m, 1H), 4.27-4.40 (m, 1H), 2.68-2.88 (m, 2H), 2.45-2.64 (m, 2H). MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[OH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[OH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccnc1O
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O)c1cccnc1O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-hydroxynicotinic acid. δH (DMSO-d6) 10.15 (1H, d, J 7.4 Hz), 8.31 (1H, dd, J 7.1, 2.0 Hz), 7.71 (1H, br s), 7.65-7.45 (3H, m), 7.16 (2H, d, J 8.4 Hz), 6.97 (2H, d, J 8.4 Hz), 6.46 (1H, t, J 6.8 Hz), 5.17 (2H, s), 4.68 (1H, m), 3.2-3.0 (2H, m); m/z (ESI, 60V) 461 (MH+).
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.CNC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:31]([CH:28]1[CH2:29][CH2:30][N:25]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: O=C(Cl)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
Diisopropylethylamine (0.35 ml, 2.0 mmol) was added in one portion to a stirred solution of dimethylamine (0.8 ml, 1.6 mmol) in DCM (2 ml) at room temperature. To this mixture was added 1-(4-nitro-benzenesulfonyl)-piperidine-4-carbonyl chloride (0.27, 0.8 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time, the mixture was diluted with DCM (20 ml) and washed sequentially by HCl (1M solution, 20 ml) and NaOH (1M solution, 20 ml) before being separated, dried (MgSO4), filtered and concentrated under vacuum to afford the title compound (0.17 g, 33% yield) as an off white solid. Tr=1.65 min m/z (ES+) (M+H+) 342.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)c2cccc(Br)c2n1
Temperature: 120 °C
Yield: 84.9 %

Procedure:
Part B: A mixture of 5.0 g (19.5 mmol) of 2-methyl-4-chloro-8-bromo-quinoline, 18.3 g (195 mmol) of phenol and 2.5 g (87%, 39 mmol) of KOH was heated at 120° C. under nitrogen for 30 min. After cooling 500 ml of CH2Cl2 was added and the mixture was extracted with 250 ml of 1N NaOH. After concentration of the organic layer in vacuo the residue was dissolved in ether and again extracted with 50 ml of 1N NaOH and 50 ml of brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. A total of 5.2 g of 2-methyl-4-phenoxy-8-bromo-quinoline was obtained as a white solid (85% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].[F-].[K+].C1OCCOCCOCCOCCOCCOC1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [F-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(F)cccc1[N+](=O)[O-]

Procedure:
To a solution of 1,2-difluoro-3-nitrobenzene from Example B1 (1.9 g, 12 mmol) in acetonitrile (75 ml) were added glycine ethyl ester hydrochloride (1.7 g, 12 mmol), potassium fluoride (1.2 g, 20 mmol), 18-crown-6 (309 mg, 1.2 mmol) and diisopropylethylamine (4.6 ml, 26 mmol). The mixture was stirred at reflux for 3 h, cooled and evaporated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80); yield 2.1 g, 73%.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1>[OH-].[Na+]>[CH:13]1([NH:12][C:10]([NH2:9])=[O:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCCc2ccccc21
Yield: 89 %

Procedure:
A mixture of 1-benzoyl-3-(1,2,3,4-tetrahydro-1- naphthyl)urea (2.0 g) and aqueous sodium hydroxide (1N; 20 ml) is stirred and heated at reflux for 2.75 hours. The mixture is then cooled in ice and the product is collected and washed with water to afford 1.15 g of the title compound, m.p. 204° to 207° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a stirred solution of tert-butyl 4-oxocyclohexylcarbamate (2 g, 9.3 mmol) in THF (40 mL) at −78° C. was added dropwise MeMgBr (10 mL of 3M/THF, 30 mmol). The reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 18 h, the reaction was treated with saturated NH4Cl aqueous solution. The solution was concentrated, taken up into CH2Cl2, washed with H2O by aid of citric acid. The organic phase was washed with saturated NaHCO3 aqueous solution, H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography to give tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate 2 as oil (1.2 g, 56%). 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 3H), 1.45 (s, overlapped 9H), 1.5˜1.8 (set of m, 10H), 3.40 (br, 1H), 4.40 (br, 1H).
Reaction SMILES: N[C@H](C1C=CC=CC=1)CC(OC)=O.[N+:14]([C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1Cl)([O-])=O.NC1C=CC=CC=1C(NC1C=CC2N=C[N:38]([CH:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:42][C:43]([OH:45])=[O:44])[C:37]=2C=1)=O>>[N+:23]([C:21]1[CH:20]=[CH:19][C:18]2[N:38]([C@H:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:42][C:43]([OH:45])=[O:44])[CH:37]=[N:14][C:17]=2[CH:22]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1
Agent: COC(=O)C[C@H](N)c1ccccc1
Product: O=C(O)C[C@@H](c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21

Procedure:
Using a similar procedure to that described in Preparation 45, the title compound (19 mg) was prepared from methyl (3S)-3-amino-3-phenylpropanoate and 2,4-dinitrochlorobenzene, and liberated as the free acid using a procedure similar to that described in Preparation II. [LCMS (Method C, Mobile Phase I) RT=2.60 min, MH+ 312].
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]12[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:23][NH:22][CH2:21][CH2:20]2.O.[OH-].[K+]>C(OCC)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:22]2[CH2:23][CH:24]3[N:19]([CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:21]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CNCCN2C1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCN2CCCC2C1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Yield: 86 %

Procedure:
To 70.6 parts of 2,2-diphenyl-4-bromobutyronitrile is added 27 parts of 1,4-diazabicyclo[4.3.0]nonane, 63 parts of demineralized water and 15.5 parts of potassium hydroxide. The mixture is stirred and heated to 75° - 80° C. and then further heated to reflux. After 3.5 hours at reflux, the mixture is cooled to about 30° C. and 180 parts of ethyl ether is added. The aqueous layer is separated and discarded. The remaining ether layer is extracted three times with 100 parts by volume portions of 1% acetic acid in water, twice with 30% solutions of hydrochloric acid in water, and twice with 50% solutions of hydrochloric acid in water. The hydrochloric acid solution extracts are combined and basified to pH 11.0 with a 50% solution of potassium hydroxide in water. The resulting oil is extracted with three 150 part portions of chloroform. The chloroform extracts are combined, washed with 100 parts of a saturated sodium chloride solution, dried over anhydrous potassium carbonate, and stripped of solvent under reduced pressure. The resulting product, 2,2-diphenyl-4-(1,4-diazabicyclo[4.3.0]non-4-yl)butyronitrile, identical to the product of Example 7, is obtained in 86% yield. Correction of this yield to reflect the purity of the 1,4-diazabicyclo[4.3.0]-nonane (86.4%) results in a yield of 99.5% for this reaction.