Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](S(C)=O)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(S(C)=O)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
1 gm (2.9 mols) of 6-ethoxy-2-methylsulfinyl-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine [m.p. 164°-165°C, prepared from 6 ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine and 30% hydrogen peroxide in dilute acetic acid] was refluxed together with 5 gm (58 millimols) of piperazine in 50 ml of ethanol for 10 minutes. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, evaporated to dryness, and the residue was recrystallized from ethanol. Yield: 0.9 gm (84.7% of theory); m.p. 220°-222°C.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.CO>[O:1]([CH2:8][C:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[O:17])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccccc1
Reactant: NC(=O)c1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1cccc(NC(=O)COc2ccccc2)c1
Yield: 83.1 %

Procedure:
To a solution of phenoxy-acetic acid (100 mg, 0.65 mmol), 3-amino benzamide (178.9 mg, 1.31 mmol), HOBt (177.7 mg, 1.31 mmol) and DIPEA (170 mg, 1.31 mmol) in DMF (6 ml) was added EDC (252 mg, 1.31 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH: MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH:MC=1:9˜2:8) to afford of 3-(2-phenoxy-acetyl-amino)-benzamide as a colorless solid (146 mg, 82% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C@@H:30]1[CH3:35])([CH3:28])[CH3:27]>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[C@@H:30]([CH3:35])[CH2:31]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CC(C)N1CCNC[C@@H]1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C(C)C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-isopropyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.50 (m, 9H) 2.33 (d, J=2.53 Hz, 3H) 2.88-3.64 (m, 5H) 3.89 (br. s., 2H) 4.22-4.92 (m, 1H) 7.53-7.69 (m, 1H) 7.70-7.79 (m, 1H) 7.84-8.79 (m, 4H) 9.49-10.25 (m, 1H). ESI-MS m/z [M+H]+ 463.3.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[NH:13])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].O>CN(C)C=O.C1CCCCC1.C(OCC)(=O)C>[CH:26]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([NH:11][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[NH:13])=[CH:7][CH:6]=2)[CH2:1]1)([CH3:28])[CH3:27]
Reactant: CC(C)Br
Reactant: N=C(Nc1ccc2c(c1)CNCC2)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CC(C)N1CCc2ccc(NC(=N)c3cccs3)cc2C1
Temperature: 40 °C

Procedure:
To a stirred solution of N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2-thiophenecarboximidamide (7.0 g, 21 mmol) in dimethylformamide (100 ml) was added potassium carbonate (14.6 g, 100 mmol). To this mixture was added 2-bromopropane (5.1 g, 42 mmol), and the mixture was then heated to 40° C. for 72 h. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with water (200 ml) and dried over magnesium sulfate. Evaporation of the solvent yielded a crude oil, which was then dissolved in hot cyclohexane (250 ml) and ethyl acetate (10 ml). Upon standing the title compound crystallized out and was collected by filtration (3.2 g), m.p. 110-111° C.
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][N:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][C:7]3[N:17]([CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:16]=[CH:15][C:8]=3[C:9]=1[S:10]2.Cl.[O:28]1[CH2:33][CH2:32]OCC1>C(O)(C)C>[CH3:4][C:5]1[CH:6]=[C:7]([NH:17][C:2]2[C:3]3[C:4]4[CH2:5][CH2:6][C:7]5[N:17]([CH2:18][CH2:19][N:20]6[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]6)[N:16]=[CH:15][C:8]=5[C:9]=4[S:10][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:8]=[CH:32][C:33]=1[OH:28]
Reactant: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(Cl)c23)CC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCN2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-3-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene (150 mg, 0.39 mmol) and 4-amino-O-cresol (71 mg, 0.58 mmol) in isopropanol (5 mL) was added 4M HCl in dioxane (0.67 mL, 2.7 mmol). The reaction mixture was sealed in a microwave reaction vessel and it was placed in a microwave instrument at 160° C. for 10 min. After it was cooled to room temperature, solvents were evaporated and the residue was dissolved in MeOH/water/DMF and purified by prep. HPLC. After drying, the TFA salt was neutralized with saturated NaHCO3 and extracted with a mixture of CHCl3:isopropanol (v/v, 3:1). The organic phase was dried over Na2SO4 and concentrated to dryness. The desired product was obtained as a pale solid (174 mg, 95%). 1H-NMR (CD2Cl2-d2) δ 8.34 (s, 1H), 7.55 (s, 1H), 7.28 (m, 2H), 6.88 (b, 1H), 6.80 (m, 1H), 4.20 (t, 2H, J=6.2 Hz), 3.38 (t, 2H, J=8.3 Hz), 3.13 (t, 2H, J=8.4 Hz), 2.85 (t, 2H, J=6.2 Hz), 2.62-2.45 (b, 8H), 2.30 (s, 3H), 2.26 (s, 3H); LCMS RT=1.89 min; [M+H]+=476.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Cl.[Cl:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16].[OH-].[Na+]>C1COCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[ClH:12].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:18][CH2:17][N:15]([CH3:16])[CH2:14][CH2:13]1
Reactant: N#CCc1ccccc1F
Reactant: CN(CCCl)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(C#N)(c2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a solution of (2-fluorophenyl)acetonitrile (15 mmol) in THF (20 mL) are successively added bis-(2-chloroethyl)methylamine hydrochloride (16 mmol), tetrabutylammonium hydrogensulfate (1.5 mmol), and 40% aq. NaOH (20 mL), then the mixture is refluxed for 5.5 h. The reaction mixture is cooled at room temperature, diluted with water, then extracted with THF. The organic extracts are washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is dissolved in ether, then HCl in 1,4-dioxane is added. The precipitate is collected by filtration to give the titled compound, which is directly used for the next reaction without further purification; 1H NMR (DMSO) δ: 2.43-2.60 (4H, m), 2.86 (3H, d), 3.20-3.28 (2H, m), 4.02-4.04 (2H, m), 7.31-7.40 (2H, m), 7.48-7.60 (2H, m), 11.16 (1H, br).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@H:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>CO>[NH2:30][C:24](=[O:25])[CH2:23][O:22][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: N
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCC(N)=O)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate (500 mg, 1.16 mmol) in MeOH (10 mL) was added NH3 (aq) (28%, 15 mL) at rt. The resulting clear solution was stirred at rt overnight. Solvent and excess ammonia was removed in vacuo to afford (R)-tert-butyl 3-((2-amino-2-oxoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (350 mg, 0.87 mmol, 75%). 1H NMR (400 MHz, CD3OD): 1.45 (s, 9H), 1.56 (m, 1H), 1.90 (m, 1H), 2.95 (m, 2H), 3.55-3.85 (m, 3H), 4.15 (m, 1H), 4.56 (m, 1H), 7.22 (m, 1H), 7.42 (m, 2H); MS (E/Z): 401 (M+H+). The diastereomers can be separated by preparative HPLC if desired.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH3:13].C1OCCOCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1>[CH2:10]([N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCBr
Reactant: O=Cc1c[nH]cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCn1cnc(C=O)c1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Imidazole-4-carboxaldehyde (10 g, 104 mmol) was added portionwise to a solution of sodium hydride (4.56 g, 60% dispersion in mineral oil, 114 mmol) in tetrahydrofuran (150 ml), and the solution stirred for 30 minutes. n-Butyl bromide (15.7 g, 114 mmol) was added portionwise, followed by 18-crown-6 (50 mg), and the reaction heated under reflux for 18 hours. Aqueous ammonium chloride solution was added to the cooled reaction and the mixture extracted with ethyl acetate (2×) and dichloromethane (2×). The combined organic extracts were then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of pentane:ethyl acetate (50:50 to 25:75), to give the title compound, 4.45 g, 28% yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([CH3:24])[C:6]([O:22][CH3:23])=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]([F:33])([F:32])[C:27]1[CH:31]=[CH:30][NH:29][N:28]=1.ClC1C(OC)=CC=C2C=1N=C(N1C=CC(C(F)(F)F)=N1)C=C2OCC1C=CC(OC)=CC=1>>[CH3:23][O:22][C:6]1[C:5]([CH3:24])=[C:4]2[C:9]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]([N:29]3[CH:30]=[CH:31][C:27]([C:26]([F:33])([F:32])[F:25])=[N:28]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(C)c(OC)ccc23)cc1
Yield: 19 %

Procedure:
7-Methoxy-4-(4-methoxy-benzyloxy)-8-methyl-2-(3-trifluoromethyl-1H-pyrazol-1-yl)-quinoline 234c was synthesized from compounds 221b and 233a, following the procedure as described for compound 234a, as a white solid in 19% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.64 (s, 3H), 3.86 (s, 3H), 3.99 (s, 3H), 5.33 (s, 2H), 6.75 (d, J=2.58 Hz, 1H), 6.98 (d, J=8.78 Hz, 2H), 7.20 (d, J=9.22 Hz, 1H), 7.48 (d, J=8.78 Hz, 2H), 7.57 (s, 1H), 8.07 (d, J=9.08 Hz, 1H), 8.88 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[Si:27]([O:15][CH2:14][C:13]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])[CH3:16])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)c1cc(N)n(-c2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.6 %

Procedure:
To a solution of above 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol (0.208 g, 0.85 mmol) in DMF (2.0 mL) was added imidazole (0.32 g, 4.7 mmol) and TBSCl (0.39 g, 2.6 mmol). The resulting mixture was stirred at RT for 5 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by chromatography to afford 3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.125 g, 42% yield) as a light yellow oil. MS (ESI) m/z: 346.3 (M+H+).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:59]/[O:60][CH3:61])/[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O:43]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:42])=[C:34]([CH:37]=[CH:38][CH2:39]I)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:62][C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1>C(Cl)Cl>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:59]/[O:60][CH3:61])/[C:27]([NH:29][CH:30]2[C:57](=[O:58])[N:32]3[C:33]([C:41]([O-:43])=[O:42])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N+:65]4[CH:66]=[CH:67][CH:68]=[C:63]([NH2:62])[CH:64]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Nc1cccnc1
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[n+]3cccc(N)c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-1, 738 mg, 0.8 mmole) and 3-aminopyridine (113 mg, 1.2 mmole) in methylene chloride (15 ml) was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and treated with a mixture of 90% trifluoroacetic acid (TFA) (8 ml) and anisole (1.6 ml) at room temperature for 1 hour, and then was concentrated and triturated with ether. The resulting crude product was purified by column chromatography using HP-20 (eluted with 10% methanol and 30% methanol) and the packing in a PrepPAK-500/C18 cartridge (Waters) (eluted with 5% methanol). The desired fraction was concentrated and lyophilized to give 38 mg (9%) of the title compound (I-1E). Estimated purity, 55%. M.p. >170° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][OH:18])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=[O:18])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2cc(CCCO)on2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Reaction time: 4 h
Yield: 59.4 %

Procedure:
3-[3-(3-nitrophenyl)isoxazol-5-yl]propan-1-ol (1.02 g, 4.1 mmol), sodium acetate (0.10 g, 1.3 mmol), and pyridinium chlorochromate (1.77 g, 8.2 mmol) were added in 30 mL of dry methylene chloride. After the reaction was continued for 4 hr at an ambient temperature, diethyl ether was added and the reaction mixture was filtered through a cellite bed. 0.6 g (64%) of the target compound was obtained by removing all the solvent and purifying by column chromatography on silica gel.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:11]1[C:19]2[NH:18][C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5]>[Pd]>[CH2:22]1[CH:16]2[CH:17]([NH:18][C:19]3[C:11]([C:9]([NH:8][C@@H:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[CH:12][CH:13]=[CH:14][C:15]=32)[CH2:20][CH2:21]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Product: COC(=O)[C@H](CO)NC(=O)c1cccc2c1NC1CCCC21
Yield: 100 %

Procedure:
Following the procedure of method 1C, methyl (2S)-3-hydroxy-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate(8.9 mmol, 2.7 g) was hydrogenated using 5% Pd/C (2 g) and concentrated HCI (10 mL) in methanol (25 mL) to yield the crude product (8.9 mmol, 2.7 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].OC(C(F)(F)F)=O.[I:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:27][C:23]=2[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[N:27][C:23]=2[CH:22]=1
Reactant: Ic1ccc2[nH]c([C@@H]3CCCN3)nc2c1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (68 mg, 0.39 mmol) and (S)-5-iodo-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole-TFA salt (100 mg, 0.32 mmol) in anhydrous DMF (2 mL) is added DIPEA (0.25 mL, 1.43 mmol) followed by HATU (142 mg, 0.37 mmol). The reaction mixture is stirred for 4 hours at room temperature. Ice is added and the product is extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue is purified by flash column chromatography on silica gel (EtOAc/MeOH 0% to 10%) to give methyl ((S)-1-((S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (150 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:35](=[O:36])[C@@H:30]([NH:29][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:31][CH2:32][S:33][CH3:34])[C@H:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
A sample of (1R,3R,4S)-(4-amino-3-propyl-cyclohexyl)-carbamic acid tert-butyl ester (1.9 mmol) was dissolved in 1:1 CH2Cl2/DMF (40 mL), and the resultant solution was charged with N-Cbz methionine (591 mg, 2.1 mmol), N,N-diethylisopropylamine (1 mL, 5.7 mmol), and BOP (1.0 g, 2.3 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1R,3R,4S)-[4-((2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (375 mg). MS found: (M+H)+=522.3.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13]CC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C>C(O)C.[OH-].[Na+]>[NH2:4][C:5]1[N:9]([CH2:10][C:11]([OH:13])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CC(=O)O
Yield: 103.6 %

Procedure:
A solution of ethyl 2-(5-acetamido-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (620 mg, 1.5 mmol) in ethanol (7 mL) and 25% NaOH (7 mL) was heated to 83° C. for 16 h. The resultant solid was filtered, washed with ethanol and water then dried in vacuo to give 2-(5-amino-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetic acid as a solid (521 mg), which was used as such in the subsequent step.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[C:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:4]=1
Reactant: [H][H]
Reactant: O=C1CCCC1=Cc1cc(C(F)(F)F)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC1Cc1cc(C(F)(F)F)ccn1

Procedure:
A solution of 2-{[4-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentan-1-one (0.513 g, 2.13 mmol) in ethyl acetate (20 mL) was added palladium on carbon (10% wt, 50% wet, 0.226 g, 0.11 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:61][C:62]1[CH:77]=[CH:76][CH:75]=[C:74]([F:78])[C:63]=1[O:64][C:65]1[CH:73]=[CH:72][C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=1>CN(C=O)C.O>[F:61][C:62]1[CH:77]=[CH:76][CH:75]=[C:74]([F:78])[C:63]=1[O:64][C:65]1[CH:73]=[CH:72][C:68]([C:69]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:70])=[CH:67][CH:66]=1
Reactant: O=C(O)c1ccc(Oc2c(F)cccc2F)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 60.6 %

Procedure:
DIPEA (46 mg, 0.36 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (62 mg, 0.14 mmol) in DMF (1 mL). HOBT (19 mg, 0.14 mmol) and EDCI.HCl (28 mg, 0.14 mmol) were then added at room temperature. After 2 minutes, 4-(2,6-difluorophenoxy)benzoic acid (30 mg, 0.12 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 40 mg (60.6% yield) of 4-(2,6-difluoro-phenoxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 94.3%, NMR Values: 1H NMR (CDCl3): δ 7.9-7.7 (m, 3H). 7.7-7.5 (m, 2H), 7.4-7.3 (d, 1H), 7.2-7.1 (m, 2H), 7.1-6.9 (m, 4H), 4.3 (dd, 1H), 4.2 (dd, 1H), 4.0-3.5 (m, 6H), 3.4 (t, 1H), 3.2 (m, 2H).