Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:27])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)[C:3]=12.Cl>O1CCOCC1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH3:27])[N:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask, 1,1-dimethylethyl 5-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (745 mg, 2.033 mmol) was added followed by 4 M HCl in dioxane (12.2 mL). The mixture was stirred overnight at room temperature. LCMS showed no more SM. The light brown colored solid in the reaction mixture was filtered, washed by 20 mL of EtOAc, dried to give the desired product as a off-white solid. LC/MS (ES) m/z=267.1 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([F:21])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+]>Br>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:21])[CH:14]=2)=[O:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Yield: 51 %

Procedure:
(4-(2-Chloroethoxy)phenyl)(3-fluoro-4-methoxyphenyl)methanone from the previous step in 20 mL 40% HBr was refluxed for 1 h., neutralized with solid Na2CO3 at 0° C., and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography (eluent: petroleum ether/EtOAc=5/1 to 2/1) over silica gel to give the subtitle compound (731 mg, 51% yield for 3 steps) as a yellow solid.
Reaction SMILES: [O:1]([CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)=[CH:24][CH:23]=1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].O>O1CCCC1.C(#N)C>[OH:1][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](OCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
368 mg (corresponding to 0.595 mmol) of 2-[4′-(2″-t-butyldiphenylsiloxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in 1.0 mL of tetrahydrofuran (THF), and 0.70 mL of a 1.0 mol/L solution in tetrahydrofuran of tetrabutylammoniumfluoride (TBAF) was added thereto. After the reaction mixture was stirred at room temperature for 2 hours, ammonium chloride aqueous solution was added, followed by addition of 5.0 mL of water and 2.0 mL of acetonitrile. Then precipitates were filtered. The filtered precipitates were washed with water and acetonitrile in this order, to obtain 226 mg (corresponding to 0.595 mmol) of 2-[4′-(2″-hydroxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1, Step 5).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH3:8])[N:3]=1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:7][C:6]1[C:2]([N:1]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[N:3][N:4]([CH3:8])[CH:5]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cc(Br)c(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-4-bromo-1-methylpyrazole (2.69 g, 15.28 mmol) and DMAP (6.16 g, 50.45 mmol) in CH2Cl2 (100 mL) at 0° C. under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (4.7 mL, 33.62 mmol) dropwise. The reaction mixture was warmed to rt and stirred for 1 hour. The reaction was quenched with water and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75, then 3/7 and 1/1) to afford bis(2,2,2-trichloroethyl) 4-bromo-1-methyl-1H-pyrazol-3-ylimidodicarbonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1.C([C@H]1NC2C(=CC(F)=CC=2)NC1=O)C>>[CH2:13]([C@@H:9]1[NH:8][C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:15][C:10]1=[O:11])[CH3:14]
Reactant: CC[C@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: CC[C@H]1Nc2ccc(F)cc2NC1=O
Product: CC[C@@H]1Nc2ccc(F)cc2NC1=O

Procedure:
(2S)-2-[(4-Fluoro-2-nitrophenyl)amino]butanoic acid was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=+33.42° (c=0.01 G/ML, DMSO); MS (ESI) m/z 195 ([M+H]+); Anal. Calcd for C10H11FN2O: C, 61.85; H, 5.71; N, 14.42. Found: C, 61.84; H, 5.72; N, 14.24.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1CC)[CH:2]=[CH2:3].[Cl:18]C1C=C(C=C(C)C=1O)C=O>>[CH2:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1[Cl:18])[CH:2]=[CH2:3]
Reactant: Cc1cc(C=O)cc(Cl)c1O
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1CC
Product: C=CCOc1c(C)cc(C(=N)NO)cc1Cl

Procedure:
The title compound is prepared in analogy to 4-allyloxy-3-ethyl-N-hydroxy-5-methyl-benzamidine starting from commercially available 3-chloro-4-hydroxy-5-methyl-benzaldehyde; LC-MS: tR=0.69 min, [M+1]+=241.10.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][OH:9])[CH3:7])[CH3:5].C(O)(C)(C)C.CC([O-])(C)C.[K+].[CH3:21][O:22][N:23]([C:28]1[C:29](Cl)=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]>CS(C)=O>[CH3:21][O:22][N:23]([C:28]1[C:29]([O:9][N:8]=[C:6]([CH3:7])[C:4](=[N:3][O:2][CH3:1])[CH3:5])=[N:30][CH:31]=[CH:32][CH:33]=1)[C:24](=[O:27])[O:25][CH3:26]
Reactant: CON=C(C)C(C)=NO
Reactant: COC(=O)N(OC)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CON=C(C)C(C)=NOc1ncccc1N(OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 70° C., a mixture of 1.2 g (9.2 mmol) of 2-methoxyimino-3-hydroxyiminobutane and 25 ml of tert-butanol was treated with 1.03 g (9.2 mmol) of potassium tert-butylate, and the mixture was stirred for 1 hour. The reaction mixture was freed from solvent under reduced pressure at approximately 40° C. The residue was introduced into 15 ml of dimethyl sulfoxide, and 2 g (9.2 mmol) of methyl N-methoxy-N-(2-chloropyridin-3-yl)carbamate, dissolved in 3 ml of dimethyl sulfoxide, were added at 50° C. The mixture was stirred for 2 hours at 100° C., and the reaction mixture was transferred to approximately 150 g of ice and extracted with tert-butyl methyl ether. The organic phases were combined, washed with water, dried, and the solvent was removed, under reduced pressure. The resulting residue was purified by column chromatography over silica gel using cyclohexane/ethyl acetate (2:1). This gave 470 mg (17%) of the title compound as a brown solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][CH2:35][C@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[CH3:34][C@H:35]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:36][CH3:37]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Yield: 84.2 %

Procedure:
A solution of DIAD (16.6 mL, 84.0 mmol) in dry THF (100 mL) was added dropwise to a cooled (ice bath) stirred mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (14.5 g, 56.2 mmol); R-(−)-sec-butanol (5 g, 67.0 mmol) and solid-supported triphenylphosphine (28 g, of 3 mmol per g loading, 84.0 mmol) in dry THF (400 mL) whilst maintaining the temperature below 10° C. The mixture was allowed to stir for 3 hours, then diluted with diethyl ether (800 mL) and filtered. Removal of the solvent gave a pale coloured oil, which was purified by column chromatography on silica, eluting with 25% ethyl acetate in hexane; to give the desired product (14.87 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.Cl.[N:12]([O-:14])=[O:13].[Na+].S([O-])([O-])=O>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1c(F)cccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 17.2 g. of 2-chloro-6-fluoroaniline hydrochloride and 12.5 ml. of concentrated hydrochloric acid in 150 ml. of water is added slowly a solution of 9 g. of sodium nitrite in 25 ml. of water. The temperature of the solution is kept below 5° at all times. This solution is then added to a stirred suspension of 18 g. of cuprocupric sulfite and 60 g. of sodium nitrite in 300 ml. of water at room temperature. The mixture is stirred for 1 hour then steam distilled until no trace of product is noted condensing in the distillate. The distillate is extracted with ether, dried (magnesium sulfate) concentrated and distilled to give 7.8 g. of product, b.p. 148°-152° at 30 mm. Gas chromatography analysis shows this to be greater than 95% pure.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:47]1[CH2:48][CH2:49][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:46]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21

Procedure:
A solution of 0.14 g 1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, 0.15 g potassium carbonate and 0.07 g (R)-3-tert-butoxycarbonylaminopiperidine in 2 ml dimethylsulphoxide is stirred for 5 h at 60° C. Then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[C:16]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)=[O:28]>C1COCC1.C(Cl)Cl>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[C:16]=1[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)[OH:28]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3CO)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3CO)ccc2c1

Procedure:
Add LAH solution (1 mL, 1 M/THF) to a stirred solution of [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (171 mg, 0.34 mmol) in THF (5 mL) at 0° C. Quench the reaction with sat. NaHCO3 and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate to yield [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol. Use the crude product without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:31])[C:28](O)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:31])[C:28]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1COCCN1
Reactant: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)O
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCOCC1
Yield: 42 %

Procedure:
Using the same procedure as in Example 44, (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (300 mg, 0.66 mmol) was reacted with morpholine to give the title compound as a white solid (144 mg, 42%); NMR Spectrum 1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrum MH+ 527.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17]O)=[N:16][C:12]=2[CH:11]=1.S(Cl)(Cl)=O.[I-].[Na+].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:15]([CH2:17][NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:16][C:12]=2[CH:11]=1
Reactant: OCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc(CNCc2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To 5-(benzoxazol-2-yl)-2-hydroxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 13-2) (168 mg, 0.481 mmol) was added thionyl chloride (1.5 mL), and this was heated to reflux with stirring for 2 hours. After the reaction was complete, this was cooled to room temperature and concentrated. The crystals obtained were suspended in tetrahydrofuran, and to this was added sodium iodide (108 mg, 0.722 mmol) and benzylamine (258 mg, 2.41 mmol), and this was heated to reflux with stirring for 1.5 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give an residue that was purified by silica gel column chromatography to yield the title compound (182 mg, 86% yield) as a colorless amorphous mass.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C=O)C>CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 99.9 %

Procedure:
To a 500 mL round-bottomed flask equipped with magnetic stirring was added 2-fluoronitrobenzene (14 g, 101 mmol), DIEA (19 mL, 110 mmol), 1-benzylpiperazine (18 mL, 110 mmol) (Aldrich) and DMF (250 mL). The reaction was stirred for 18 h, diluted with 400 mL of EtOAc and washed with 300 mL each of 10% NaHCO3, H2O, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to yield 1-(2-nitrophenyl)-4-benzylpiperazine (30 g). Calc'd for C17H19N3O2: 297.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=4)[CH:29]=[CH:30][C:31]=3[O:32]CC)=[O:25])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:35]4[CH:36]=[C:37]([C:45]([F:46])([F:47])[F:48])[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=4)[CH:29]=[CH:30][C:31]=3[OH:32])=[O:25])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Agent: BrB(Br)Br
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2O)n1
Yield: 72.3 %

Procedure:
4-Hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (48 mg) was prepared from 4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (69 mg, 0.10 mmol) and boron tribromide (0.25 mL, 0.25 mmol, 1.0 M solution in DCM) following the general procedure P.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: Fc1ccc2nnc(N3CCCC3)n2c1
Temperature: 175 °C
Yield: 46.1 %

Procedure:
A mixture of Intermediate 24b (515 mg, 3.00 mmol), pyrrolidine (0.85 g, 12.0 mmol) and DMA (10 mL) was heated to 175° C. for 4 h using microwave irradiation. After cooling, the solvent was removed in vacuo and the resulting residue purified by FCC, using 0 to 15% MeOH in DCM, to provide the title compound as a brown gum (285 mg, 26%). LCMS (Method 3): Rt 1.95 min, m/z 207 [MH+].
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:15]=2)[CH2:11][OH:12])=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:20][C:19]1[C:14]([NH:13][C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH2:11][OH:12])=[N:15][C:16]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H](CO)c3ccc(F)cc3)n2)n[nH]1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc(N)c(N[C@@H](CO)c3ccc(F)cc3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of saturated ammonium chloride (3 ml) was added slowly to a suspension of (R)-2-(4-fluorophenyl)-2-(6-(5-methyl-1H-pyrazol-3-ylamino)-3-nitropyridin-2-ylamino)ethanol (Method 63, 0.29 g, 0.78 mmol) and zinc dust (0.25 g, 3.9 mmol) in a mixture of MeOH-THF (1:1, 20 ml). The mixture was stirred at 25° C. for 1 hour. Saturated ammonium acetate solution (5 ml) was added and the mixture was stirred for another 30 minutes. The Zn dust was removed by filtration and the cake was washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml) and dried over sodium sulfate. After removal of solvent, the title compound was obtained which was used directly for the next step without purification. MS: Calcd.: 342. Found: [M+H]+ 343.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH2:9]3)=[CH:4][C:3]=2[O:2]1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([N:14]4[CH2:19][CH2:18][N:17]([C:21]5[N:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:16][CH2:15]4)[CH2:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: c1c2c(cc3c1OCO3)CC(N1CCNCC1)CC2
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(C3CCc4cc5c(cc4C3)OCO5)CC2)nc1
Yield: 59.2 %

Procedure:
A solution of 2.6 g of 1-(6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthyl) piperazine, 1.5 g of 2-chloropyrimidine and 1.4 g of potassium carbonate in 50 ml of anhydrous dimethylformamide, was heated at 130° C. for 3 hours. Then the reactional mixture was cooled, the so-formed salt was filtered out and the solvent was evaporated under reduced pressure. The so-obtained residue was taken up with 30 ml of a normal solution of methanesulphonic acid and 15 ml of chloroform. The mixture was decanted off, and the acid solution was alkalized with potassium carbonate. The base was extracted with chloroform. The solution was dried and the solvent was evaporated. There were obtained 3 g of crude product which recrystallized in 40 ml of ethanol gave 2 g of 1-(6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthyl)-4-(2pyrimidinyl) piperazine, beige crystals melting at 134°-135° C. The corresponding monomethanesulfonate melts at 218°-225° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.[CH3:24][C:25]1[C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:27][C:28]([CH3:32])=[C:29]([CH3:31])[CH:30]=1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([N:36]1[CH2:37][CH2:38][N:33]([C:26]2[C:25]([CH3:24])=[CH:30][C:29]([CH3:31])=[C:28]([CH3:32])[N:27]=2)[CH2:34][CH2:35]1)=[O:11]
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)nc1C
Yield: 25 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 175, the title compound (64.2 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:13])[NH2:12])([CH3:10])[CH3:9])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH2:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of (1-carbamoyl-1-methyl-ethyl)-carbamic acid tert-butyl ester (945 mg, 4.67 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10.0 mL, 64 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated in vacuo to afford 882 mg of the title compound as a white solid, isolated as the TFA salt, m/z 103.2 [M+1]+.