Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][C:21](=[O:22])[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Br)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CC(=O)O
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc([N+](=O)[O-])cc2N1
Temperature: 110 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
To a stirred solution of 4-nitrobenzene-1,2-diamine 2 (1.0 g, 6.53 mmol) in acetic acid (20 mL) was added ethyl 3-(3-bromophenyl)-3-oxopropanoate 1 (1.75 g, 6.53 mmol) at RT under inert atmosphere. The resulting reaction mixture was heated to 110° C. and stirred for 12 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude was purified by silica gel column chromatography (eluent: 25% EtOAc/Hexane) to afford compound 3 (0.91 g, 39.5%) as yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 10.91 (bs, 1H), 8.25 (s, 1H), 8.09-8.01 (m, 3H), 7.82 (d, J=6.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57-7.48 (m, 1H), 3.67 (s, 2H). MS (ESI): 361 [M+1]+
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1>O1CCCC1>[CH3:1][C@:5]1([OH:4])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@](C)(O)C[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 28.6 %

Procedure:
Methylmagnesium bromide (3 M solution in ether, 1.2 mL, 3.6 mmol) was added to a solution of tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (328 mg, 1.2 mmol), in tetrahydrofuran (20 mL) at 0° C. and the resulting mixture was stirred at this temperature one hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with ethyl acetate (80 mL). The organic portion was separated, washed with water, then brine solution, dried over sodium sulfate, filtered and concentrated. The residue purified by silica gel chromatography (25% to 70% ethyl acetate in hexane gradient) to give the first eluting isomer assigned as (±)-tert-butyl (2R,4S)-4-methyl-2-phenylpiperidin-4-ol-1-carboxylate (100 mg, 29% yield), LC-MS for C17H25NO3: 292 (MH+); and the second eluting isomer assigned as (±)-tert-butyl (2R,4R)-4-methyl-2-phenylpiperidin-4-ol-1-carboxylate (120 mg, 35% yield), MS (EI) for C17H25NO3: 292 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 35.4 %

Procedure:
Potassium carbonate (3.2 g, 12.3 mmol) was added to a solution of 4-chloro-2-nitro-phenol (6.0 g, 34.6 mmol) in DMF (60 mL). The mixture was cooled to 0° C. 2-Chloro-N,N-dimethyl ethyl amine hydrochloride (9.96 g, 69.1 mmol) was added in portions. The reaction mixture was allowed to warm to rt, stirred for 4 h, heated to 95° C., stirred for 16 h, allowed to cool to rt, quenched by addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH, 98:2) to provide 3.0 g of the title compound. tR: 0.12 min (LC-MS 2); ESI-MS: 245 [M+H]+ (LC-MS 2); Rf=0.29 (CHCl3/MeOH, 9:1).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1COCC1>[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:2][O:3][CH3:4])=[CH:34][CH:33]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(OC(F)F)cc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
A suspension of methoxymethyl triphenylphosphonium chloride (6.69 g, 19.5 mmol) in THF (200 mL) was cooled to ca. −20° C. n-BuLi (2.5 M in hexanes, 7.2 mL, 18 mmol) was added in portions over 5 min and the orange-red reaction mixture was stirred for an additional 15 min. 4-difluoromethoxybenzaldehyde (2.58 g, 15.0 mmol) in THF (50 mL) was added at −10° C. and the reaction mixture was stirred at this temperature for 30 min and then at room temperature for 19 h. Water (100 mL) was added and the mixture was concentrated under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by three times repeated chromatography on silica gel. (Horizon™, flash system from Biotage™. Column: Flash 40+M, 40×150 mm. Eluent: 3% ethyl acetate in heptane. Combination of pure fractions and concentration in vacuo afforded 1.60 g (53%) of the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=O)[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=[S:36])[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nc(Nc2cccc(C3(C)COCC(=O)N3)c2)c2ccc(Br)cc21
Solvent: Cc1ccccc1
Product: Cn1nc(Nc2cccc(C3(C)COCC(=S)N3)c2)c2ccc(Br)cc21
Temperature: 120 °C

Procedure:
To a suspension of 5-[3-(6-bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholin-3-one (52.6 mg, 0.127 mmol) in toluene (3 ml) was added Lawesson's reagent (51.2 mg, 0.127 mmol) and the reaction mixture was heated at 120° C. for 2 h. The solvent was evaporated and the title compound was purified by FC (cyclohexane:EtOAc 100:0 to 80:20).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[OH:24][CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]NC2C=CC=CC=2)=[CH:34][CH:33]=1)[CH2:28][CH3:29]>CN(C=O)C>[OH:24][CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:36][CH:37]=1)[CH2:28][CH3:29]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCN(CCO)CCc1ccc(NNc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCN(CCO)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and {4-[2-(N-(2-hydroxyethyl)-N-ethyl-amino)-ethyl]-phenylamino}-aniline in DMF.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10](=[O:28])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:27])[CH2:17][NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].[Cl:36][CH2:37]S(OCl)(=O)=O>C(Cl)Cl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:28])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:27])[CH2:17][NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:37][Cl:36])=[O:24])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(CCl)OCl
Reactant: O=C(O)CCCC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: O=C(CCCC(=O)OCCl)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 87.1 %

Procedure:
To a solution of 3.09 g of Compound (23) obtained in the step (b) in 70 ml of methylene chloride were added 1.85 g of sodium bicarbonate in 70 ml of water, 249 mg of tetrabutylammonium hydrogen sulfate and 1.57 g of ClCH2SO3Cl, and the reaction mixture was stirred for 140 minutes at room temperature. After reaction, the organic layer was separated and washed with 4% sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3.00 g of [N-(4-chloromethyloxycarbonylbutanoyl)glycyl]-L-proline p-nitrobenzyl ester as pale yellowish oil. Then, a mixture solution of 2.86 g of the compound obtained above and 1.83 g of sodium iodide in 20 ml of acetonitrile was refluxed for 2 hours. After reaction, the solvent was removed and the resulting residue was dissolved in 70 ml of ethyl acetate. The organic layer was washed with 0.1N sodium thiosulfate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloride-acetone) to give 2.35 g of [N-(4-iodomethyloxycarbonylbutanoyl)glycyl]-L-proline P-nitrobenzyl ester [Compound (24)] as yellowish oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]I.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>O1CCOCC1>[CH2:14]([O:13][P:12]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: COCCOCCOCCI
Reactant: CCOP(OCC)OCC
Solvent: C1COCCO1
Product: CCOP(=O)(CCOCCOCCOC)OCC

Procedure:
{2-[2-(2-Methoxyethoxy)ethoxy]ethyl}iodide (6.64 g, 24.3 mmol) and P(OEt)3 (4.22 ml, 24.3 mmol) were dissolved in 1,4-dioxane (30 ml) and stirred under reflux for 24 hours. Volatiles were distilled in vacuo (150° C., 0.01 torr) to give the crude material as a thick yellow oil. Column chromatography (silica gel, EtOAc:MeOH 95:5 elution) afforded the desired product as a pale yellow oil. Yield 1.0 g, 15%. Alternative synthesis using {2-[2-(2-Methoxyethoxy)ethoxy]ethyl}iodide (5.00 g, 18.2 mmol) and P(OEt)3 (10 ml, excess) under microwave irradiation (100 W, 1 hr) gave higher yield after column chromatography (3.06 g, 10.7 mmol, 59%). 1H NMR (CDCl3, 400 MHz, 298 K): δ 4.08 (m, 4H), 3.67 (d of t, JH-P=10 Hz, JH-H=7 Hz, 2H), 3.60 (m, 6H), 3.50 (m, 2H), 3.36 (s, 3H), 2.09 (d of t, JH-P=20 Hz, JH-H=7 Hz, 2H), 1.28 (t, J=7 Hz). 13C {1H} NMR (CDCl3, 100 MHz, 298 K): δ 71.72, 70.35, 70.30, 69.97, 64.92, 61.44 (d, JC-P=6 Hz), 58.82, 26.77 (d, JC-P=138 Hz), 16.22 (d, JC-P=6 Hz). 31P{1H} NMR (CDCl3, 162 MHz, 298 K): δ 29.23. MS (FAB, m/z): 285 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 285.15395 (285.14670).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1N
Solvent: CC#N
Product: NC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 83.6 %

Procedure:
2-Amino-3-nitrobenzamide (4.0 g) in warm anhydrous acetonitrile (1.25 L) was treated with N-chlorosuccinimide (3.1 g) at 60° C. under nitrogen for 20 hours. The mixture was allowed to cool to room temperature and filtered. The filter cake was washed with acetonitrile and dried to provide the title compound (3.98 g, 84%). MS (DCI/NH3) m/z 216 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8]1.[NH3:27]>CO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:27])=[O:2])[CH2:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Reactant: N
Solvent: CO
Product: NC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Temperature: 100 °C
Yield: 75 %

Procedure:
4-[(R)-3-(4-Benzyl-phenoxy)-pyrrolidin-1-yl]-butyric acid methyl ester (200 mg, 0.566 mmol) was taken into 7N ammonia in methanol solution (5 mL) in a pressure tube. The reaction was sealed and heated at 100° C. for 48 h. The mixture was then cooled to room temperature and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with a gradient of 10% methanol in dichloromethane to 15% methanol in dichloromethane) to obtain the title product (145 mg, 75%); LCMS; m/z 340 (M+1); 1H NMR (400 MHz, DMSO); δ 1.58-1.74(m, 3H), 2.04-2.08 (m, 2H), 2.19-2.24 (m, 1H), 2.33-2.41 (m, 3H), 2.54-2.58 (m, 1H), 2.61-2.65 (m, 1H), 2.78-2.82 (m, 1H), 3.85 (s, 2H), 4.77-4.80 (m, 1H), 6.68 (s, 1H), 6.78 (d, J=8.8, 2H), 7.11 (d, J=8.4, 2H), 7.17-7.22 (m, 3H), 7.25-7.29 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])=[C:5]2[C:22](O)=[O:23])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH2:33])[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH:33][C:22]([C:5]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[O:23])[CH2:28][O:27]1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCC(CONC(=O)c2c(Nc3ccc(I)cc3F)c3cnccc3n2C2CC2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a heterogeneous mixture of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (160.0 mg, 0.37 mmol) and O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (113.1 mg, 0.77 mmol, 2.1 eq) in anhydrous N,N-dimethylformamide (5.7 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (278.3 mg, 0.74 mmol, 2.0 eq) and N,N-diisopropylethylamine (0.25 mL, 1.46 mmol, 4.0 eq), and the resulting homogeneous reaction mixture was stirred under N2 at RT for 16 h. The reaction mixture was quenched with MeOH (2 mL), and the crude material was absorbed onto silica. The crude mixture was purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the product as an orange waxy solid (75.4 mg; 36.4%). LC-MS (method C): [M+H]+=567.2, RT=0.73 min.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C[C:15]([CH3:18])([O-:17])C.[K+]>C1COCC1>[CH2:11]([OH:12])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][CH2:18][CH2:15][OH:17]
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCOCCO
Agent: [K+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCO
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1 L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over ˜30 min). The reaction mixture was then stirred for 1 h and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, ˜200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2×500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[OH:14][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:15][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil.
Reaction SMILES: C(=O)(OCC(F)(F)F)OCC(F)(F)F.FC(F)(F)C[NH:18][C:19](=[O:38])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30](=[O:37])[NH:31]CC(F)(F)F)[CH:23]=1>>[C:30](=[O:37])([O:29][CH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:19](=[O:38])[NH2:18])[CH:23]=1)[NH2:31]
Reactant: O=C(NCC(F)(F)F)OCc1cccc(COC(=O)NCC(F)(F)F)c1
Agent: O=C(OCC(F)(F)F)OCC(F)(F)F
Product: NC(=O)OCc1cccc(COC(N)=O)c1
Yield: 93.5 %

Procedure:
The reaction was carried out in the same manner as Example 3 except for using 37.1 g (0.1642 mol) of bis(2,2,2-trifluoroethyl) carbonate (to be referred to as “BTrFC” hereinafter) synthesized in the above Synthesis Example 2 in place of BTFC, and it was confirmed that m-xylylene bis(2,2,2-trifluoroethyl carbamate) (to be referred to as XDC-2 hereinafter) was generated as the main product (XDA base yield 93.5%). Structural assignment of the product XDC-2 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of XDC-2, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH:39]([CH3:41])[CH3:40]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CC(C)CBr
Agent: Cl
Product: CC(C)Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and isobutyl bromide (0.326 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 19, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.11 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([N:18]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(N=Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Reaction time: 30 h

Procedure:
A solution of 15.6 g (100 mmol) 2-amino-4-fluoronitrobenzene, 22.5 g (180 mmol) 4-fluorobenzylamine and 20.2 g (220 mmol) triethylamine in 150 ml dimethylsulfoxide is heated with stirring and under an inert gas atmosphere for 30 hours to 60°-70° C. When the reaction time is completed, the solvent is distilled off in a vacuum, the residue is taken up in 500 ml 0.5N hydrochloric acid and the mixture is stirred intensively at room temperature for 30 minutes. The precipitated solid is suction filtered and subjected to hot steam extraction with toluene. The product crystallizing out of the toluene after the mixture has been allowed to stand for twelve hours at 0°-4° C. is suction filtered and dried in a vacuum. 22.2 g (85 % of theory) are obtained. After being left to stand for 12 hours at 0°-4° C., 2-amino-4-(4-fluorobenzylamino)-nitrobenzene crystallizes out of the toluene phase as orange-yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH2:12])=[N:3]1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[CH2:12][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:3]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1nn(C)c2ccccc12
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1nn(C)c2ccccc12

Procedure:
A solution of compound 2 (1.1 g, 7 mmol) in toluene (5 mL) was treated with ethyl diazoacetate (1.2 g, 10 mmol) and stirred at reflux overnight under N2. The mixture was concentrated and the residue was purified by gradient elution on silica gel (PE: EA=5:1) to afford the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].O.CC(O)C>[OH-].[Na+].C1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:3][CH:2]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 77.4 %

Procedure:
A vigorously stirred mixture of 34 g (0.25 mol) of 4-tolylboronic acid and 34 g (0.17 mol) of 2-bromo-1-nitrobenzene in a mixture of 170 mL of 5N sodium hydroxide, 57 mL of water, 215 mL of 2-propanol and 1080 mL of benzene was treated with 11.9 g of (tetrakis)triphenylphosphine palladium(0). The two-phase mixture was heated at reflux for three hours. The cooled reaction mixture was filtered through Celite and the filter cake washed with fresh benzene. The organic layer was separated and washed with water (3×), dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue (46.1 g) purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (20:1), to give 28.05 g of the product.