Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:9]1([N+:22]([O-:24])=[O:23])[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:13]2[CH2:21][C@H:10]1[CH:11]=[CH:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:34].[Na+].OO>C1COCC1.CCO>[C:1]([C@@:9]1([N+:22]([O-:24])=[O:23])[C@H:10]2[CH2:21][C@H:13]([CH2:12][C@@H:11]2[OH:34])[C@H:14]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)[C@@]1([N+](=O)[O-])[C@@H]2C=C[C@@H](C2)[C@H]1c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccccc1)[C@]1([N+](=O)[O-])[C@H](c2ccccc2)[C@H]2C[C@H](O)[C@@H]1C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of Compound 9 (2.20 g, 6.90 mmol) in THF (18 mL, 0.38M) was treated with 9-BBN (8.62 mmol, 1.25 equiv) in THF (17.25 mL, 0.5M) and the mixture was allowed to stir at 25° C. under N2 for 10 hours. The resulting mixture was treated successively with 4.15 mL of EtOH, 1.5 mL of 20 percent aqueous NaOH, and 1.65 mL of 50 percent aqueous H2O2. The reaction solution was warmed at 50° C. for one hour, recooled to 25° C., and partitioned between EtOAc (200 mL) and H2O (200 mL). The EtOAc layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5×15 cm, 10-25 percent EtOAc-hexane gradient elution) afforded the major isomer Compound 10 (1.29 g, 55.5 percent; Rf =0.32, 20 percent EtOAc-hexane) and Compound 11 (1S*,2R*,4S*,5R*,6S*-5-benzoyl-2-hydroxy-5-nitro-6-phenyl-bicyclo[[2.2.1]heptane, 400 mg, 17.2 percent; Rf =0.26, 20 percent EtOAc-hexane) as white solids cleanly separated from one another in a 3.2:1 ratio (1.69 g total, 2.32 g theoretical, 73 percent). For Compound 10: mp 168°-169° C. (EtOAc-hexane, colorless needles); 1H NMR (CDCl3, 250 MHz) δ7.38 (d, 2H, J=8.2 Hz), 7.31-6.94 (m, 8H), 4.33 (d, 1H, J=2.4 Hz, C5-H), 3.85 (d, 1H, J=6.8, C2-H), 3.29 (s, 1H, C1-H), 2.63 (d, J=11.3 Hz, C7-H syn to ketone), 2.46 (d, 1H, J=4.3 Hz, C4-H), 2.26-2.16 (m, 2H), 1.67-1.60 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ189.9, 138.8, 133.7, 133.0, 128.9, 128.5, 128.3, 127.8, 127.4, 105.0, 69.3, 55.5, 55.4, 44.6, 42.1, 35.7; IR (neat) vmax 3331, 2968, 2900, 1689, 1538, 1444, 1353, 1234, 1096, 1063 cm-1 ; FABHRMS (NBA-NaI) m/e 360.1230 (C20H19NO4+Na+ requires 360.1212). Anal. Calcd for C20H19NO4 : C, 71.20; H, 5.68; N, 4.15. Found: C, 71.13; H, 5.89; N, 4.10. For Compound 11: 1H NMR (CDCl3, 250 MHz) δ7.34 (d, 2H, J=8.0 Hz), 7.25-6.90 (m, 8H), 4.18 (m, 2H), 3.25 (m, 1H), 2.62 (d, 1H, J=11.2 Hz), 2.26 (s, 1H), 2.12 (d, 1H, J=11.4 Hz), 1.80-1.62 (m, 2H), 1.45 (m, 1H); FABHRMS (NBA-CsI) m/e 470.0368 (C2H19NO4 +Cs+ requires 470.0368).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=C)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].I([O-])(=O)(=O)=[O:15].[Na+]>C(O)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCC1(C(=O)OC)CCCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1(CC=O)CCCCC1
Reaction time: 24 h
Yield: 31 %

Procedure:
To a solution of 1-allyl-cyclohexanecarboxylic acid methyl ester (4.0 g, 21.5 mmol) in isopropanol (35 mL) was added a solution of sodium periodate (10.1 g, 47.3 mmol) in H2O (35 mL) followed by the addition of osmium tetroxide (16 mg, 0.065 mmol). More isopropanol (30 mL) and H2O (35 mL) was added and the resulting suspension was stirred for 24 hours. Then, the reaction mixture was poured into ice/H2O (200 mL) and extracted with EtOAc (2×200 mL) in a separatory funnel. The organic layers were combined and dried over Na2SO4, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (10 to 60% EtOAc/heptane) to provide 1.24 g (31% yield over two steps) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][NH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[OH:25]O>C(O)(=O)C.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[S:15](=[O:25])[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[NH:18][CH2:19]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Reactant: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2=O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (20 mg, 0.058 mmol) in acetic acid (500 μL) was treated with hydrogen peroxide (12 μL of aq. 30% w/w, 0.12 mmol) and stirred at room temperature for 2 h. The reaction was diluted with DMF and purified by HPLC (10-99% CH3CN/5 mM HCl) to provide N-(4-tert-butyl-3-hydroxy-phenyl)-1-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxamide (8 mg, 38% yield). LC/MS m/z 359.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-methoxyethylamine according to general procedure 1 providing the amino compound (432 mg, 74%) as a yellow solid; Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 3.68 (t, J=5.4 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.43 (s, 3H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:19][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-(9H-fluoren-9-ylmethyl) ester (5 g, 14.2 mmol) in CH2Cl2 (50 mL) was added DMF (0.5 mL) and the resulting solution was cooled to 0° C. To this solution oxalyl chloride (3.6 g, 28.44 mmol) was added dropwise and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to afford (9H-fluoren-9-yl)methyl 4-(chlorocarbonyl)-piperidine-1-carboxylate (5 g, 95%) as brown liquid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc(CN2CCC(O)C2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of pyrrolidin-3-ol (3.8 g, 44 mmol) and 3-methoxybenzaldehyde (5.0 g, 37 mmol) in 1,2-dichloroethane (100 mL), was added sodium triacetoxyborohydride (15.5 g, 73 mmol) portionwise at 0° C. Acetic acid (2.8 mL, 44 mmol) was subsequently added. The reaction mixture was warmed to 45° C. and stirred overnight. A saturated solution of sodium bicarbonate was added and the resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product, 1-(3-methoxybenzyl)pyrrolidin-3-ol, obtained (6.0 g, 79%) as a yellow oil, was used as such in the next reaction: 1H NMR (CDCl3, 400 MHz) δ 7.28-7.18 (m, 1H), 6.92-6.86 (m, 2H), 6.82-6.76 (m, 1H), 4.32 (tdd, J=2.3, 5.0, 7.3 Hz, 1H), 3.83-3.78 (m, 3H), 3.59 (s, 2H), 2.86 (dt, J=4.9, 8.6 Hz, 1H), 2.68 (d, J=9.8 Hz, 1H), 2.53 (dd, J=5.3, 10.3 Hz, 1H), 2.45 (br s, 1H), 2.30 (dt, J=6.5, 8.9 Hz, 1H), 2.24-2.13 (m, 1H), 1.78-1.68 (m, 1H); ESI MS (m/z) 208 [M+H]+.
Reaction SMILES: [Li+].[OH-:2].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:20](=[O:21])[CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:9][CH2:8]1)=[O:6]>O1CCOCC1.O>[C:15]([N:16]([CH3:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]([NH:14][CH2:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:4])=[O:6])[CH2:8][CH2:9]1)=[O:21])([OH:27])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3N(C)C2=O)CC1
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)O)c1ccccc1CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
LiOH (1.3 mmol, 0.03 g) was added to a solution of trans-4-(1-Methyl-2,4-dioxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (0.84 mmol, 0.29 g) in dioxane (3 mL) and water (3 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with DCM, then HCl (1N) was added until reached pH 1, then extract with DCM (3×10 mL) and AcOEt (3×10 mL). The organic layers were washed with brine (2×10 mL) dried over Na2SO4 collected together and concentrated under reduced pressure to give the title compound in quantitative yield (0.29 g).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:28]O>Cl.O1CCOCC1.ClCCl>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][CH:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:28])=[O:6]
Reactant: CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of the lithocholic acid 1 (25.1 g, 66.4 mmol) in anhydrous methanol (100 mL), 4M HCl in 1,4-dioxane (100 mL) was added and the reaction mixture stirred at ambient temperature overnight. The reaction mixture became heterogeneous. The reaction mixture was diluted with dichloromethane (300 mL) and the organic layer was washed with saturated NaHCO3 (2×200 mL). The organic layer was concentrated and dried under high vacuum overnight to provide the pure ester as a white solid (25.7 g, 97%). The analytical and spectral data were consistent with that of reported values (Rensen, Patrick C. N.; van Leeuwen, Steven H.; Sliedregt, Leo A. J. M.; Van Berkel, Theo J. C.; Biessen, Erik A. L. Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asialoglycoprotein Receptor. Journal of Medicinal Chemistry (2004), 47(23), 5798-5808.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]COCC.[Mg].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([CH3:33])([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CCCCCCC(=O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCC(C)(O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 1.75 g of 1-(3,4-dibenzyloxyphenyl)-3-nonanone in 10 ml of tetrahydrofuran was cooled to 0° to 5° C. and then an ether solution of a Grignard reagent prepared from 0.24 g of metallic magnesium and 1.7 g of methyl iodide was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 1.6 g of 1-(3,4-dibenzyloxyphenyl)-3-methyl-3-nonanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccccc1-c1nc[nH]c1-c1ccccc1Cl
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 23.6 %

Procedure:
4,5-Bis(2-chlorophenyl)imidazole (1.2 g) (Chem. Ber., 1959, 92, 338-343) and ethyl 8-bromooctanoate (2.1 g) were reacted in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 4,5-bis(2-chlorophenyl)-1-(7-ethoxycarbonyl-heptyl)imidazole (0.45 g, 23.7%) as an oil. NMR d (CDCl3) . 1.0-1.8(11H, m, 4×CH2, CH3), 2.2(2H, t, CH2C=0), 3.8 (2H, m, N--CH2), 4.1(2H, q, CH20C=O), 7.1-7.45 (8H, m, ArH), 7.69 (1H, s, N=CH)ppm
Reaction SMILES: C([O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:8])C1OC1.N1CC[O:18]CC1>>[OH:18][O:5][C:6](=[O:14])[C@H:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:8]
Reactant: C1COCCN1
Reactant: N[C@@H](CCC(=O)O)C(=O)OCC1CO1
Product: N[C@@H](CCC(=O)O)C(=O)OO
Reaction time: 8 h
Yield: 220.5 %

Procedure:
To a solution of 712 mg (1.81 mmol) of glycidyl ester 28 and 0.316 mL (3.62 mmol, 2.0 equiv) of morpholine was added 1 g of neutral alumina. The reaction mixture was stirred overnight and then filtered and concentrated. Purification by flash chromatography (30×150 mm silica gel, 200 mL of 1.5% and 200 mL of 2.5% methanol/dichloromethane) provided 651 mg (75%) of the title compound: 1H NMR (300 MHz, CD3OD) δ7.38-7.29 (m, 5H), 5.09 (s, 2H), 4.19-3.97 (m, 3H), 3.69-3.60 (m, 5H), 2.56-2.41 (m, 8H), 2.22-2.08 (m, 1H), 1.97-1.84 (m, 1H), 1.45 (s, 9H); MS(FAB) 481 (M+1), 425.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:11])[NH2:10])=[CH:5][CH:4]=1.Cl[CH:15]([C:19](=O)[CH3:20])[C:16](=[O:18])[CH3:17]>CCO>[CH3:20][C:19]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[S:11][C:15]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Yield: 78.5 %

Procedure:
4-(Trifluoromethyl)benzene-1-carbothiamide (5.03 g, 24.5 mmol) was dissolved in 30 ml of EtOH and treated with 1.05 eq of 3-chloro-2,4-pentanedione (3.46 g, 25.7 mmol); the mixture was kept at 55-60° C. over night. Reducing the total volume to ˜¼ and cooling to 0° C. triggered crystallization. Filtration and washing with a tiny amount of cold EtOH afforded 5.49 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (79%) as yellow crystals of, MS: 285 (M+), MP: 89-90° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25](=O)[NH2:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]#[N:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(N)=O)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C#N)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 3-butyl-4-[[4-[1-carbamoyl-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step A) in phosphorus oxychloride (25-30 equivalents) is stirred at 0° C. under N2 as triethylamine (2.2 equivalents) is added dropwise over about 1 hours. After the addition is complete, the mixture is gradually warmed to room temperature and then heated to reflux for about 45 minutes or until TLC indicates complete reaction. The cooled mixture is concentrated in vacuo, and the residue is partitioned between ice-water and an organic solvent, such as ether, ethyl acetate, or toluene. The organic phase is washed with dilute NaOH and then with H2O. The organic solution is dried over MgSO4, filtered, and concentrated to give the title compound, which is used directly or may be purified by chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].[F:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.N1C(C)=CC=CC=1C>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][CH2:13][CH2:12][F:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NCCF)cc(C)c1Br
Temperature: 120 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenylamine (400 mg, 2 mmol), toluene-4-sulfonic acid 2-fluoro-ethyl ester (567 mg, 2.6 mmol) and 2,6-lutidine (429 mg, 4.0 mmol) in DMA (5 ml) was heated with stirring at 120° C. for four hours. The mixture was quenched with water and then extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (4-bromo-3,5-dimethyl-phenyl)-(2-fluoro-ethyl)-amine (262 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCOCC1)C.FC(F)(F)C(O)=O.[Cl:61][C:62]([Cl:77])([Cl:76])[C:63]1[O:67][N:66]=[C:65]([N:68]2[CH2:73][CH2:72][CH:71]([CH2:74][NH2:75])[CH2:70][CH2:69]2)[N:64]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([NH:75][CH2:74][CH:71]1[CH2:72][CH2:73][N:68]([C:65]2[N:64]=[C:63]([C:62]([Cl:77])([Cl:76])[Cl:61])[O:67][N:66]=2)[CH2:69][CH2:70]1)=[O:17]
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: NCC1CCN(c2noc(C(Cl)(Cl)Cl)n2)CC1
Agent: CCN1CCOCC1
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
Product: Cc1ccc(C(=O)NCC2CCN(c3noc(C(Cl)(Cl)Cl)n3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (200 mg, 0.615 mmol) was dissolved in 5 ml DMF. After cooling to −15° C. HATU (257.34 mg, 0.676 mmol) and N-ethylmorpholine (283.3 mg, 2.46 mmol) were added. The mixture was stirred at 0° C. for 15 min. and 30 min. at room temperature. C-[1-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yl]-methylamine; compound with trifluoro-acetic acid (254.4 mg, 0.615 mmol) was added and the mixture stirred for 1 hour and evaporated under reduced pressure. The residue was dissolved in sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated. The crude material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][C:8]=2[CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:39][O:38][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:15]2[CH2:16][CH2:17][CH:12]([C:10]3[O:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:8]([CH2:18][O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[N:9]=3)[CH2:13][CH2:14]2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Reactant: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccccc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccccc4)o3)CC2)cc1S(N)(=O)=O
Temperature: 100 °C

Procedure:
To 4-[5-phenyl-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidine (0.750 g), prepared as in Intermediate 5, in dioxane is added 5-(2-chloro-ethyl)-2-methoxy-benzenesulfonamide (0.716 g), prepared as in Intermediate 1, Nal (0.429 g) and DIEA (1.15 ml). After heating at 100° C. for 18 hours, the reaction mixture is partitioned between EtOAc and dilute NaHCO3 solution. The organic phase is washed with saturated brine, dried (NaSO4) and concentrated. The residue is dissolved in CHCl3 (20 mL) and preadsorbed onto silica gel. Purification by flash chromatography on silica gel using a MeOH-EtOAc gradient (2-10%), followed by radial chromotography using a MeOH-CH2Cl2 gradient (1-5%) and crystallization from CH2Cl2 -EtOAc affords the title compound as a white solid.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]([O-])=O.[Na+]>O.Cl>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][NH2:17])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
p-Benzyloxyphenylhydrazine hydrochloride was prepared by the method of Mentzer, et al., [C.A. 48:33412]. Thus, p-benzyloxyaniline hydrochloride (72.6 g) was diazotized with conc. HCl (174 ml) and sodium nitrite (23.2 g) in water (40 ml) at 0° C. A solution of stannous chloride (169.3 g) in conc. HCl (435 ml) was added rapidly and the reaction mixture stirred for two hours. The solid product was filtered and washed with absolute ethanol, then partially dissolved in boiling methanol/ethanol (1:1) and filtered hot, yielding 52.5 g of p-benzyloxyphenylhydrazine hydrochloride.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:12][Mg]Br.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]([OH:11])[CH3:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1cc2ccoc2cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
Under an argon atmosphere, furo[2,3-c]pyridine-5-carbaldehyde (488 mg, 3.31 mmol) was dissolved in tetrahydrofuran (11 mL), and added methylmagnesium bromide (5.5 mL (1.0 M in THF solution), 4.97 mmol) under ice-cold conditions. Then, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was added 1N-aqueous solution of hydrochloric acid under ice-cold conditions, and then a saturated aqueous solution of sodium hydrogen carbonate was added. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (356 mg (yield 66%)) was obtained as a yellow solid.