Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[C:25]([O:24][C:23]([NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([NH:1][C:2]2[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:18]1)=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCc1c(N)cc(Cl)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(NC2CCC(NC(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-ethylbenzoate (365 mg, 1.7 mmol) in 1,2-dichloroethane (20 ml) under nitrogen, was added tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol) followed by acetic acid (587 μl, 10.3 mmol). The solution was stirred for 10 minutes before the portionwise addition of sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 1 hour. The resulting solution was stirred at room temperature for 17 hours, before treating with tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol). The reaction mixture was stirred for 30 minutes and then treated with sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 2.5 hours. The reaction mixture was stirred at room temperature for a further 26 hours before addition of deionized water (40 ml). The mixture was neutralised with solid NaHCO3 (2.95 g) and was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (35 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-18% EtOAc/Heptanes) to give as an oil the title compound (623 mg, 85%) as a mixture of cis/trans isomers. LC-MS 46.1%, 2.61 min (3.5 minute LC-MS method), m/z=411.1, 413.1 and 50.2%, 2.66 min (3.5 minute LC-MS method), m/z=411.1, 413.1; 1H NMR (500 MHz, Chloroform-d) d ppm 7.05 (dd, J=7.09, 2.05 Hz, 1H) 6.68 (t, J=2.36 Hz, 1H) 4.36-4.63 (m, 1H) 3.88 (d, J=3.31 Hz, 3H) 3.62-3.78 (m, 1H) 3.49 (br. s., 1H) 3.23 (br. s., 1H) 2.63-2.76 (m, 2H) 2.07-2.18 (m, 2H) 1.77-1.89 (m, 2H) 1.69 (br. s., 1H) 1.46 (s, 9H) 1.27 (m, 3H) 1.13-1.24 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16](=[O:23])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2cccnc2)CC1
Yield: 93.5 %

Procedure:
1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine (940 mg, 2.97 mmol, from Procedure 38, Step B) was hydrogenated using 5% Pd/C in 95% ethanol at atmospheric pressure. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 50:50 v/v hexanes/ethyl acetate gave 884 mg of the title compound as a colorless syrup. For the title compound:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9](C(OC(C)(C)C)=O)[CH:8]3[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:7]3[C:6]=2[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[NH:9][CH:8]3[CH2:18][CH2:19][NH:20][CH2:21][CH:7]3[C:6]=2[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc(Br)c1N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2cc(Br)c3c(c2)C2CNCCC2N3)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A 100 mL round bottom flask was charged with a solution of di(tert-butyl) 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (0.27 g, 0.45 mmol) in CH2Cl2 (5 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (5 mL) was added via pipette, the ice bath was removed, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction was then concentrated in vacuo, and the residue was partitioned between 5 N NaOH and ethyl acetate (2X). The organics were combined, dried with MgSO4, filtered and concentrated to give 280 mg of a crude yellow oil. The crude was purified on a 40 g silica Biotage column using 5% methanol in CH2Cl2 as the eluent to give 151 mg (85%) of 6-bromo-8-(2,4-dichlorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=2 Hz, 1 H), 7.26 (m, 3 H), 7.10 (s, 1 H), 4.08 (m, 2 H), 3.28 (m, 1 H), 3.14-2.86 (m, 4 H), 1.93-1.80 (m, 3 H); IR (diffuse reflectance) 2937, 2851, 1615, 1572, 1460, 1359, 1314, 1303, 1237, 1102, 1032, 869, 816, 761, 744 cm−1. OAMS supporting ions at: ESI+398.8; HRMS (FAB) calcd for C17H15BRCL2N2 +H1 396.9874, found 396.9867.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:21]=3)=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1>>[CH:27]([O:26][C:24]1[N:23]=[C:22]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[CH:2][C:3]([C:4]([NH:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:6])=[CH:7][CH:8]=3)=[O:36])=[CH:15][CH:16]=2)[N:25]=1)([CH3:28])[CH3:29]
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)ccc1C(=O)O
Product: CC(C)Oc1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)cc2)nc(N2CCOCC2)n1
Yield: 27 %

Procedure:
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (200 mg, 0.42 mmol) and 4-amino-1-methylpiperidine following the procedure as outlined in Experimental 71, 65 mg (27% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 574.68.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].I[CH2:23][CH2:24][CH3:25].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:23][CH2:24][CH3:25]
Reactant: CNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 140 °C

Procedure:
A suspension of 10-[(2RS)-1-methylamino-2-propyl]-2-phenothiazinecarbonitrile (4.7 g), 1-iodopropane (1.55 cc) and sodium hydrogen carbonate (2 g) in dimethylformamide (47 cc) is heated for 6 hours to a temperature of 140° C. After cooling, the reaction mixture is diluted with ethyl acetate (200 cc), washed with distilled water (4×30 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual oil (5.2 g) is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (70:30 by volume) (1 liter) of cyclohexane and ethyl acetate and collecting 60-cc fractions. The combined fractions 6 to 14 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbonitrile (4.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC#N>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]([CH3:21])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CI
Product: Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (4.0 g, 12.8 mmol), iodomethane (2.74 g, 9.2 mmol), and K2CO3 in CH3CN (60 mL) was stirred at room temperature under a blanket of nitrogen overnight. Upon completion of the reaction, ethyl acetate (200 mL) was added and the organic layer was washed with H2O (200 mL), dried over Na2SO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 5-bromo-3-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid: mp 98-99° C.; 1H-NMR (CDCl3) δ 7.7 (d, 1H, J=8.5 Hz), 7.27 (bs, 2H), 7.09 (d, 1H, J=2 Hz), 3.4 (s, 3H), 1.7 (s, 9H); MS (ES) m/z 349([M+Na]+, 20%), 351([M+Na]+, 20%); Anal. Calc. For C13H15BrN2O3: C, 47.73, H, 4.62, N, 8.56. Found: C, 47.46, H, 4.5, N, 8.29.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:17]([CH2:18][CH3:19])=[C:16]([CH3:20])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>>[CH2:21]([NH:23][C:24]([N:15]1[C:16]([CH3:20])=[C:17]([CH2:18][CH3:19])[C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[N:14]1)=[O:25])[CH3:22]
Reactant: CCN=C=O
Reactant: CCc1c(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]c1C
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(CC)c1C
Yield: 31.9 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole with ethyl isocyanate was carried out in the same manner as in Example 158, to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4-ethyl-5-methylpyrazole-1-carboxamide (0.36 g, yield: 31.9%). mp: 101-102° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.03 (t, J=7.6 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H), 2.25 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 3.38 (dq, J=5.9 and 7.3 Hz, 2H), 6.85-7.05 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]([C:12]3[C:17]([C:18]4[CH:19]=[C:20]5[CH:26]=[N:25][NH:24][C:21]5=[N:22][CH:23]=4)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CCO.[Pd]>[CH:1]1([C:6]2[CH:7]=[C:8]([C:12]3[C:17]([C:18]4[CH:19]=[C:20]5[CH:26]=[N:25][NH:24][C:21]5=[N:22][CH:23]=4)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(c2cccc(-c3ncccc3-c3cnc4[nH]ncc4c3)c2)CCC1
Agent: [Pd]
Solvent: CCO
Product: c1cc(-c2ncccc2-c2cnc3[nH]ncc3c2)cc(C2CCCC2)c1

Procedure:
5-(2-(3-cyclopentenylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (130 mg) was hydrogenated with Pd/C (15 mg) in EtOH (15 mL) over a period of 10 h under balloon H2 after degassing and back filling the flask with the hydrogen. The reaction mixture was filtered through celite and purified by preparative HPLC to provide 5-(2-(3-cyclopentylphenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. 1H NMR (DMSO-d6): δ 8.84 (d, 1H, J=4.7 Hz), 8.41 (d, 1H, J=7.9 Hz), 8.16 (app s, 2H), 8.14 (app s, 1H), 7.89 (app t, 1H, J=7.5 Hz), 7.23 (app s, 2H), 7.22-7.20 (m, 1H), 7.08 (s, 1H), 2.80 (q, 1H, J=8.2 Hz), 1.75-1.68 (m, 2H), 1.48-1.39 (m, 4H), 1.17-1.07 (m, 2H).LCMS: rt 5.13 min (A), purity 97%, MS (m/e) 341 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Temperature: 110 °C
Yield: 33.6 %

Procedure:
(R)-2-methyl-piperazine (3.88 g, 38.70 mmol), 2-bromo, 5-fluoro benzotrifluoride (8.55 g, 35.18 mmol), tris(dibenzylidineacetone)dipalladium (0) (32.0 mg g, 0.35 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (657.0 mg, 1.06 mmol) and sodium tert-butoxide (5.07 g, 52.77 mmol) were charged to a reaction flask. Toluene (40 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated up at 110° C. for 5.0 hours. Reaction was complete as determined by TLC. The reaction mixture was diluted with dichloromethane, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine as a light brown oil (3.1 g, 33.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C[OH:40]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:40])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[N:14]([CH3:38])[N:13]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CO
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(CO)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of sixteen 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 20 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 1.4 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][C:38]=1[CH:39]=[O:40])[O:29][CH2:30][CH2:31][CH2:32][C:33]([O-:35])=O.[Li+].Cl.[N+:43]([C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1)([O-:45])=[O:44]>CN(C=O)C.C(N(CC)CC)C>[NH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][C:38]=1[CH:39]=[O:40])[O:29][CH2:30][CH2:31][CH2:32][C:33]([NH:51][CH2:50][C:49]1[CH:48]=[CH:47][C:46]([N+:43]([O-:45])=[O:44])=[CH:53][CH:52]=1)=[O:35]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(OCCCC(=O)[O-])ccc1C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(OCCCC(=O)NCc2ccc([N+](=O)[O-])cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (114.1 mg) was added to a 1 mL DMF solution of lithium 4-(3-amino-4-formylphenoxy)-butanoate (68.7 mg), and the reaction was shaken at room temperature for 1 hour. The resulting solution was then added to a 1 mL DMF solution of 4-nitrobenzylamine HCl salt (56.6 mg) and triethylamine (84 μL), with another 1 mL DMF to help transfer. The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was partitioned between 4 mL of 10% NaCl(aq) and 8 mL of EtOAc. The phases were separated and the aqueous layer was extracted again with 8 mL EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure, affording a crude orange oil. The crude oil was purified by silica gel flash column chromatography with gradient elution of 0-10% MeOH/DCM to give the desired product as a light yellow solid. MS (ESI+): m/z 358.2. 1H NMR (400 MHz, CDCl3): 9.70 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.26 (dd, J=2.2 Hz, 8.8 Hz, 1H), 6.20 (br, 2H), 6.03 (d with br, J=2.0 Hz, 2H), 4.54 (d, J=6.0 Hz, 2H), 4.02 (t, J=5.8 Hz, 2H), 2.47 (t, J=7.0 Hz, 2H), 2.17 (quintet, J=6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): 192.0, 172.2, 164.4, 152.2, 147.2, 145.8, 137.8, 128.2, 123.9, 113.9, 105.3, 98.9, 66.7, 42.8, 32.5, 24.8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[NH:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1.O>CN(C)C=O>[CH2:7]([N:10]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]1)[CH3:8]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(CC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.9 %

Procedure:
3.7 g (26.8 mmoles) of anhydrous potassium carbonate and 4.2 g (26.6 mmoles) of ethyl iodide were added to a solution of 1.5 g (10.7 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 20 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.6 g (yield: 88.9%) of ethyl 1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=C>>[CH3:10][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]/[CH:3]=[CH:2]\[CH2:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: C=COc1ccc(OC)cc1
Reactant: C=CCc1ccccc1
Product: COc1ccc(O/C=C\Cc2ccccc2)cc1
Reaction time: 16 h
Yield: 55.8 %

Procedure:
Following the general procedure, allyl benzene (50.0 mg, 0.423 mmol, 7) was treated with p-methoxyphenyl vinyl ether (127 mg, 8.46 mmol) and 1.2 mol % of in situ-generated complex la (51.0 μL, 0.10 M, 5.08 μmol; final substrate concentration=8.3 M) and allowed to stir for 16 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (100% hexanes to 100:1 hexanes:Et2O) to afford 10a (56.8 mg, 0.236 mmol, 56.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 3027 (w), 3000 (w), 2950 (w), 2908 (w), 2834 (w), 1664 (m), 1502 (s), 1464 (m), 1453 (m), 1441 (m), 1384 (m), 1212 (s), 1179 (m), 1088 (m), 1064 (m), 1034 (m), 989 (m); NMR (400 MHz, CDCl3): δ 7.33-7.25 (4H, m), 7.24-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.84 (2H, m), 6.42 (1H, dt, J=6.0, 1.6 Hz), 4.96 (1H, td, J=7.6, 6.0 Hz), 3.80 (3H, s), 3.58 (2H, dd, J=7.6, 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ 155.4, 151.7, 141.9, 141.2, 128.6, 128.5, 126.0, 117.6, 114.8, 110.6, 55.9, 30.4; HRMS (ESI+) [M+NH4]+ calcd for C16H20NO2. 258.1494, found: 258.1491.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([O:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: CS(=O)(=O)OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 82 %

Procedure:
In substantially the same manner as in Reference Example 12, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol was allowed to react with methanesulfonyl chloride to give 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl methanesulfonate. The yield was 82%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 121-122° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]([OH:13])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.ON1C2C=CC=CC=2N=N1.[OH:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]([NH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCCOc1ccc(C(=O)O)cc1OCCCCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(C(=O)NCCc2ccc(O)cc2)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.2 %

Procedure:
3,4-Dihexyloxybenzoic acid (161 mg, 0.5 mmol) and 1-hydroxy-benzotriazole hydrate (45.9 mg, 0.3 mmol, 0.6 eq) were dissolved in DMF (5 ml), and to this solution were successively added 2-(4-hydroxyphenyl)ethylamine (82 mg, 0.6 mmol, 1.2 eq) and WSC hydrochloride (114 mg, 0.6 mmol, 1.2 eq) at room temperature. The mixture was stirred at room temperature for 15 hours. This reaction mixture was poured into ethyl acetate (75 ml), washed with water (5 ml×3) and saturated brine (15 ml). The organic layerwas dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=50/1) to give 3,4-dihexyloxy-N-[2-(4-hydroxyphenyl)ethyl]benzamide (230 mg). The obtained solid was recrystallized from ethyl acetate-hexane to give 3,4-dihexyloxy-N-[2-(4-hydroxyphenyl)ethyl]benzamide (194 mg, 88%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:3]([F:17])[C:2]=1[N:1]=[C:18]=[S:19]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Yield: 65 %

Procedure:
The title compound is prepared from N-(3-amino-4-chloro-2-fluoro-benzyl)-2,2-dimethyl-propionamide, 1,1′-thiocarbonyldi-2-pyridone in analogy to step Af.