Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1CCN1CCCCC2C=C(NC(C3SC=CC=3)=N)C=CC1=2.O=[C:29]1[N:35]([CH2:36][CH2:37][N:38]2[CH2:43]C[CH2:41][CH2:40][CH2:39]2)[C:34]2[CH:44]=[CH:45][C:46]([NH:48][C:49]([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)=[NH:50])=[CH:47][C:33]=2CC[CH2:30]1>>[N:38]1([CH2:37][CH2:36][N:35]2[C:34]3[C:33](=[CH:47][C:46]([NH:48][C:49]([C:51]4[S:52][CH:53]=[CH:54][CH:55]=4)=[NH:50])=[CH:45][CH:44]=3)[CH2:30][CH2:29]2)[CH2:39][CH2:40][CH2:41][CH2:43]1
Reactant: N=C(Nc1ccc2c(c1)CCCC(=O)N2CCN1CCCCC1)c1cccs1
Agent: CN1CCCC1CCN1CCCCc2cc(NC(=N)c3cccs3)ccc21
Product: N=C(Nc1ccc2c(c1)CCN2CCN1CCCC1)c1cccs1

Procedure:
A solution of compound 3 (0.40 g, 1.531 mmol) and Pd—C (0.162 g, 0.153 mmol, 10% wt) in dry ethanol (5 mL) was purged with hydrogen gas. The reaction was stirred at room temperature over night under hydrogen atm. (balloon pressure). Then the reaction mixture was filtered through a celite pad and washed with ethanol (35 mL). The filtrate (compound 4) was treated with imidate 5 (0.873 g, 3.06 mmol) and stirred over night at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel: 2% methanol: 98% CH2Cl2 followed by 5% 2M NH3 in methanol: 95% CH2Cl2, to give a greenish/yellow solid (230 mg, 44%). 1H-NMR (DMSO-d6) δ 7.68 (dd, J=0.9, 3.6 Hz, 1H), 7.55 (dd, J=0.9, 5.1 Hz, 1H), 7.07 (dd, J=3.6, 4.8 Hz, 1H), 6.62 (s, 1H), 6.50-6.45 (m, 2H), 6.23 (s, 2H), 3.33-3.27 (m, 2H), 3.11 (t, J=6.9 Hz, 2H), 2.84 (t, J=8.1 Hz, 2H), 2.62 (t, J=7.5, 2H), 2.55-2.45 (m, 4H), 1.70-1.65 (m, 4H); ESI-MS (m/z, %): 341 (MH+, 100), 244 (45), 127 (57), 98 (38); ESI-HRMS calculated for C19H25N4S (MH+): Calculated: 341.1794, Observed: 341.1788; HPLC purity: 95.3%.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[C:10]1([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[OH:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccnc1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Product: CCCCn1ccnc1C(O)(c1ccccc1)c1ccc(F)cc1

Procedure:
Procedure as described in 1), only using N-n-butylimidazole and 4-fluorophenyl phenyl ketone.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29](O)=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[CH3:47][NH2:48].C1COCC1>CCOC(C)=O>[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29]([NH:48][CH3:47])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CN
Reactant: O=C(O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reaction time: 0.08 h
Yield: 56 %

Procedure:
TEA (0.461 mL, 3.33 mmol) and T3P (50 wt. % in EtOAc, 0.989 mL, 1.66 mmol) were added to a solution of {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29, 372 mg, 0.83 mmol) in EtOAc (5 mL). The mixture was stirred for 5 min. Methanamine in THF (1.248 mL, 2.50 mmol) was added and the mixture was stirred at rt for 2 h. EtOAc (50 mL) was added and the mixture washed with Na2CO3 (40 mL), HCl (1 M, 30 mL) and brine (30 mL), dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm) to give the title compound (215 mg, 56%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].B([F:60])(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].B(F)(OB([O-])[O-])[O-].N1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1.F[N+]1C=CC=CC=1>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:60])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: [O-]B([O-])OB([O-])F
Agent: F[n+]1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 11 %

Procedure:
Erythromycin A (0.5 g, 0.681 mmole) was dissolved in glacial acetic acid (4 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 1.2 mL) while the temperature was maintained below 20° C. N-fluoropyridinium pyridine heptafluorodiborate (0.25 g, 0.75 mmole) was added and stirring continued for an additional 2 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford an 11% yield of crude flurithromycin. Although the yield was only 11%, this example demonstrates operation of the invention with N-F fluorinating agents derived from pyridine since with a co-solvent no flurithromycin is formed. (See Comparative Example 4).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Cl.[C:12]1(Cl)[C:18](=O)C(Cl)=C(Cl)[C:14](=O)[C:13]=1Cl.C(=O)/C=C/C>C(O)CCC.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]2[C:3]=1[N:4]=[C:13]([CH3:14])[CH:12]=[CH:18]2
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: COc1ccc(Cl)c(N)c1
Agent: C/C=C/C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCO
Product: COc1ccc(Cl)c2nc(C)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 214.5 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with 2-chloro-5-methoxyaniline (50 g, 317 mmol), n-butanol (120 mL), concentrated hydrochloric acid (37%, 90 mL), and chloranil (tetrachloro-1,4-benzoquinone) (78 g, 317 mmol). The resulting solution stirred for 1 h at 100° C. in an oil bath. A solution of (E)-crotonaldehyde (28.9 mL, 349 mmol) in n-butanol (50 mL) was added dropwise over 1 h. The resulting solution stirred for 1 h at 100° C. in an oil bath and was then cooled to 70° C. Tetrahydrofuran (650 mL) was added, and the reaction mixture stirred for 1 h at 70° C. and was then cooled to 0° C. The resulting precipitate was held at 0-5° C. for 1 h. The mixture was filtered, the solids were washed with cold (ca. 0° C.) THF (2×350 mL), and then dried in an oven to afford 8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as a yellow solid. MS (ES, m/z): 208 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:14])[CH3:15]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 57.1 %

Procedure:
{2-[2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine (0.128 g, 0.35 mmol) was treated with SnCl2.2H2O (0.319 g, 1.39 mmol, 4.0 equiv.) in EtOH (20 mL), in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.067 g, 0.20 mmol, 56%) as an oil. LCMS m/z (%)=339 (M+H79Br, 78), 341 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 7.68 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (s, 1H), 7.45-7.51 (m, 2H), 4.62-4.82 (m, 2H), 3.76 (s, 3H), 3.65-3.76 (m, 2H), 2.87 (s, 6H). The intermediate {2-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine was prepared in the following manner:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 90 °C
Yield: 83 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20 g, 80 mmol) and 4-chlorophenylboronic acid (15.6 g, 100 mmol) in toluene/EtOH (2:1, 600 mL) at RT under argon was added (Ph3P)4Pd (1.85 g, 1.8 mmol) and 2 M aqueous Na2CO3 solution (160 mL, 320 mmol). The resulting suspension was heated at 90° C. for 16 h with stirring. HPLC/MS indicated about 4% of the 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one still remained. After cooling the reaction mixture to RT, the solution was extracted with CH2Cl2 (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to obtain pure title compound, 2-Benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one, (21.7 g, 83%) as a white solid. MS [M+H]+ 327; HPLC retention time=3.85 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.I[C:13]1[CH:14]=[C:15]2[N:21]=[CH:20][N:19]([CH2:22][C:23]3[CH:39]=[CH:38][C:26]4[N:27]=[C:28]([NH:30][C@@H:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]5[OH:37])[S:29][C:25]=4[CH:24]=3)[C:16]2=[N:17][CH:18]=1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.CO.[Cu]I>[N:7]1([C:13]2[CH:14]=[C:15]3[N:21]=[CH:20][N:19]([CH2:22][C:23]4[CH:39]=[CH:38][C:26]5[N:27]=[C:28]([NH:30][C@@H:31]6[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]6[OH:37])[S:29][C:25]=5[CH:24]=4)[C:16]3=[N:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: c1cn[nH]c1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)cnc43)cc2s1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-n5cccn5)cnc43)cc2s1
Temperature: 110 °C
Yield: 63.6 %

Procedure:
To a stirred solution of CuI (14 mg, 0.0053 mmol), K2CO3 (102 mg, 0.74 mmol), and pyrazole (30 mg, 0.44 mmol) in 2 mL of DMF under argon was added (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Step 2 of Example 96 (150 mg, 0.30 mmol) and trans-N1,N2-dimethylcyclohexane-1,2-diamine (21 mg, 0.15 mmol). The reaction mixture was then heated at 110° C. overnight. The mixture was cooled to rt, diluted with MeOH, and purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (85 mg, 64%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.92 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 8.57 (d, J=2.5 Hz, 1H), 8.50 (d, J=2.5 Hz, 1H), 7.96 (d, J=7.4 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.20-7.27 (m, 1H), 6.58 (s, 1H), 5.52 (s, 2H), 4.74 (br s, 1H), 3.51 (br s, 1H), 2.03 (d, J=12.3 Hz, 1H), 1.80-1.95 (m, 1H), 1.52-1.72 (m, 2H), 1.08-1.33 (m, 4H). LCMS (ESI) m/z 446 (M+H)+.
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])[S:4][CH3:5].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1>>[C:7]([NH:6][C:3](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[S:4][CH3:5])#[N:8]
Reactant: NCCSCc1nccs1
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of dimethylcyanodithioimidocarbonate with 2-[(2-aminoethyl)thiomethyl]thiazole by the method described in Example 3(d) gave N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea. Fusion of this compound (2.15 g) with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (2.02 g) on the steam bath for 6 hours, followed by chromatographic purification on a column of silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluant afforded the title compound. (Found: C, 45.7; H, 5.4; N, 24.5% C15H21N7S3 requires: C, 45.5; H, 5.4; N, 24.8%)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2C(NC2SC=CN=2)=O)O1.[CH3:37][C:38]1[CH:51]=[CH:50][C:41]([C:42]([NH:44][C:45]2[S:46][CH:47]=[CH:48][N:49]=2)=[O:43])=[CH:40][C:39]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:42]([C:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[C:38]([CH3:37])=[CH:51][CH:50]=1)=[O:43]
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Agent: CC1(C)OB(c2ccccc2C(=O)Nc2nccs2)OC1(C)C
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)cc2)o1

Procedure:
Example 38 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-N-(thiazol-2-yl)-benzamide (Intermediate 22) with propan-2-ol as the solvent.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: COCCOc1ccc(OCC2CO2)cc1
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Solvent: CC(C)O
Product: COCCOc1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 10.2 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene and 11.0 g of 5-[2-(benzylamino)-propoxy]salicylamide in 200 ml of isopropanol is refluxed for 24 hours. By concentration of the solution by evaporation, crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]-propan-2-ol is obtained as an oil which is used in its crude state for debenzylation.
Reaction SMILES: C[CH:2]([N:11](C([O-])=O)[C:12]([O:14][C:15](C)(C)C)=[O:13])[C:3]1[C:4]([CH3:10])=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:15][O:14][C:12](=[O:13])[NH:11][CH2:2][C:3]1[C:4]([CH3:10])=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: Cc1nc(Cl)ccc1C(C)N(C(=O)[O-])C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCc1ccc(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl methyl[(6-chloro-2-methylpyridin-3-yl)methyl]imidodicarbonate (830 mg, 2.64 mmol) was taken up in a mixture of CH2Cl2 (8.0 ml) and TFA (2.0 ml) and stirred at room temperature for 1 h. The solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (25-100% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1 H), 7.85 (m, 2 H), 7.46 (m, 4 H), 7.27 (m, 4 H) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].C(C1NC=CN=1)(C1NC=CN=1)=O.[C:26]([O:30][C:31]([CH2:33][C:34](=[N:36]O)[NH2:35])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[NH2:36][C:34](=[N:35][O:10][C:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:12])[F:13])=[O:11])[CH2:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32]
Reactant: CC(C)(C)OC(=O)CC(N)=NO
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(N)=NOC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
30 g of 4-trifluoromethyl-3-pyridinecarboxylic acid is initially charged in 150 ml of dry THF and, a little at a time, admixed with 25.3 g of carbonyl-diimidazole. The mixture is stirred at room temperature for 30 min. 27.2 g of tert-butoxycarbonylacetamide oxime dissolved in 150 ml of THF are then added dropwise. The mixture is stirred overnight, the solvent is evaporated and the residue is taken up in ethyl acetate, washed three times with 1 M sulfuric acid and once with saturated sodium bicarbonate solution. Concentration of the ethyl acetate phase gives 28 g of the product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(O)CCC>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:12]=[C:11]([CH3:13])[C:5]3[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:20]=1
Reactant: Cc1cc(N)cc2oc(=O)n(C)c12
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
300 mg (1.70 mmol) 6-amino-3,4-dimethyl-3H-benzoxazol-2-one, 276 mg (1.90 mmol) 4,6-dichloropyrimidine and 0.77 mL (60 μmol) TEA were combined in 5.0 mL 1-butanol and the mixture was stirred for 1 h at 100° C. The reaction mixture was cooled to RT, evaporated down and the residue was triturated in diethyl ether. The precipitate was washed with water and dried i. vac.
Reaction SMILES: [Na].[NH2:2][OH:3].Cl.[F:5][C:6]([F:11])([F:10])[CH2:7][C:8]#[N:9]>CO>[F:5][C:6]([F:11])([F:10])[CH2:7][C:8](=[N:2][OH:3])[NH2:9]
Reactant: N#CCC(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(CC(F)(F)F)=NO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a flask containing sodium (45.87 mmol, 2.5 g) in MeOH (10 ml), a suspension of NH2OH.HCl (45.87 mmol, 3.2 g) in MeOH (11 ml) was added using a dropping funnel. After addition, the mixture was stirred for 15 min. The suspension was filtered to remove the precipitated NaCl. The filtrate was cooled to 0° C. and 3,3,3-trifluoropropionitrile (45.87 mmol, 5 g) was added. The reaction mixture was stirred for 1 h. The solvent was evaporated under reduced pressure. The crude product was proceeded to the next step without purification. Yield 3.0 g.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:25])[C@@H:10]([OH:24])[CH2:11][N:12]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:13])C1C=CC=CC=1.CC(O)=O>CO.CCOCC.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH3:25])[C@@H:10]([OH:24])[CH2:11][N:12]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH3:13]
Reactant: C[C@H]([C@@H](O)CN(C)CCCc1ccc(F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](N)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Pd(OH)2 was carefully wetted down under N2 with 10 mL of MeOH then the product of Step f (1.15 g) dissolved in 40 mL of MeOH was added followed by 50 mL of HOAc. The mixture was hydrogenated overnight on a Parr shaker at 50 PSI. Worked up by filtering off the catalyst under N2 through a fiberglass filter paper and vacuum. The filtrate was stripped to obtain an oily residue which was dissolved in 25 mL of Et2O and washed 2 times with 1N NaOH, 1 time with brine, dried (Na2SO4) and stripped to give 0.57 g of a light yellow oil. MS (ESI) detects (M+H)+=255.