Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccccc2F)cc1
Yield: 83.2 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.634 g, 0.006001 mol) was allowed to react with hydroxylamine hydrochloride (0.500 g, 0.00720 mol) in the presence of sodium carbonate (0.763 g, 0.00720 mol) in absolute ethanol to give 1.434 g of 4-(2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale yellow solid; mp 150.0-151.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.I[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:23][CH2:24][CH3:25])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CCCI
Reactant: CN1C(=O)C(c2ccncc2)(c2cccc(O)c2)N=C1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOc1cccc(C2(c3ccncc3)N=C(N)N(C)C2=O)c1
Yield: 97.2 %

Procedure:
To a stirred solution of 2-amino-5-(3-hydroxyphenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (0.13 g, 0.46 mmol) in acetone (20 mL) and DMF (1 mL) is added 1-iodopropane (0.07 mL, 0.69 mmol) and Cs2CO3 (1.50 g, 4.60 mmo). After refluxed for 1 hour, the solvent is evaporated and the crude material was purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 97/3) to give the title compound (0.145 g, 97%) as a solid. mp: 173-175° C.; MS(+) ES: 325 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21](Cl)=[O:22])[CH:8]=2)[CH:3]=1.[CH2:24]([NH2:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([NH:40][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:22])[CH:8]=2)[CH:3]=1
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 30 °C
Yield: 35.9 %

Procedure:
A dispersion of 6.5 g of 2-hydroxy-3-phenylaminocarbonyl-6-chlorocarbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 9.2 g of n-hexadecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 30 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.8 g of 2-hydroxy-3-phenylaminocarbonyl-6-n-hexadecylaminocarbonyl naphthalene (decomposition point: 257.2° C.).
Reaction SMILES: C(O)(C)(C)C.[CH3:6][O:7][CH2:8][CH:9]([NH2:12])[CH2:10][CH3:11].Cl[C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:24])[C:17]([CH3:23])=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][CH2:8][CH:9]([NH:12][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[C:16]([CH3:24])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:10][CH3:11]
Reactant: CCC(N)COC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CCC(COC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-2-Amino-1-butanol [100 grams, prepared according to D. Pitre and E. B. Grabitz, Chimia 23, 399 (1969)] was added in a dropwise manner to a stirred solution of tert-butanol (800 ml.) containing potassium tert-butoxide (126 grams). After warming this mixture to 70° C. to 80° C. for 2 hours, methyl iodide (175 grams) was added slowly at temperatures below 50° C. The suspension which formed was then stirred with refluxing overnight. After removal of the solid phase by filtration, the filtrate was fractionally distilled to give (-)-1-(methoxymethyl)propylamine contaminated with traces of tert-butanol, boiling point 125° C. to 147° C./760 mm. This amine was then allowed to react with 4-chloro-3,5-di-nitro-o-xylene, as described earlier, to give the desired product as a bright yellow solid with melting point 42.5° to 44° C., [α]D25° =137.6° (c 2.504, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][CH:43]([CH3:52])[C@H:44]([NH2:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:51][C@@H:44]([CH:43]([CH3:52])[CH3:42])[CH2:45][N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)[C@H](N)CN1CCCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CN1CCCC1)NC(=O)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
4-Chlorobenzoic acid (1.061 g, 6.78 mmol), TBTU (2.25 g, 7.01 mmol) and DIPEA (20.3 mmol) was mixed in DMF (25 mL). After 10 min was (S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.962 g, 6.16 mmol), which is commercially available, added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (1.48 g, 82%). 1H NMR (400 MHz, CDCl3) δ 0.97, 1.80, 1.94-2.32, 2.47-2.76, 2.80-3.01, 4.13, 6.66, 7.41, 7.80. Total no of protons: 23. LCMS (M+H)+: 295.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:22][CH:21]=[CH2:20])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1
Reactant: C=Cc1c(NC)nc(Cl)nc1C(=O)c1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(O)(c1ccccc1)c1nc(Cl)nc(NC)c1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone (142 mg) in THF (2.6 mL) at rt was added allylmagnesium bromide (1.0 M solution in THF, 1.1 mL) dropwise, and the reaction mixture was stirred at rt for 30 min. The reaction was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by prep. TLC eluting with 30% EtOAc/Hexanes to give the title compound as a colorless oil (133 mg). LC-MS (M−H2O+H)+=298.18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])[CH3:6])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:6])([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)S(=O)(=O)c1cccs1
Product: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1cccs1

Procedure:
2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2-sulfonyl)- propionic acid ethyl ester (3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil; MS 339.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[N:10]2[CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(n1)NC(=O)CC2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 7-(methyloxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (4.974 g, 27.9 mmol) in DMF (100 ml) at 0° C. under argon was treated with sodium hydride (60%, 1.340 g, 33.5 mmol) and allowed to stir at 0° C. for 20 min. The reaction mixture was then treated with (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (7.60 g, 29.3 mmol) and then then allowed warm slowly to rt and stirred at rt for 1 h. Water (5 ml) was then added. Reaction was evaporated, saturated aqueous NaHCO3 (500 ml) was then added and the mixture was extracted with DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([NH:8][C:9]([NH2:17])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=S)c1N1CCOCC1
Reactant: N
Solvent: CCO
Product: Cc1cccc(NC(N)=S)c1N1CCOCC1

Procedure:
Reaction of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methyl-2-morpholinophenyl)thiourea (m.p. 178°-179° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCCCCCBr)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 96.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (642.7 mg, 2.24 mmol) and N-cyclopropyl-11-bromoundecanesulfonamide (873.0 mg, 2.46 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-11-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]undecanesulfonamide (1210.0 mg) as a pale yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][CH3:7].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][N:6]([CH3:7])[C:12](=[O:14])[CH3:13]
Reactant: CNCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of (3,4-dichlorobenzyl)-methylamine (0.50 g, 2.63 mmol) (Shapiro et al. J. Amer. Chem. Soc., (1959) 81, 3725) in a mixture of tetrahydrofuran (20 ml) and 40% aqueous sodium acetate (10 ml) was cooled to 0–5° C. (ice bath) and treated with a solution of acetyl chloride (0.3 g in tetrahydrofuran) added dropwise over 5 min. After 1 h at 0–5° C., the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and distillation of the residue in vacuo gave 0.51 g (83% yield) of the title amide as a clear oil: bp 110–120° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers: 2.36 and 2.39 (3H, 2 s, COCH3), 3.16 (3H, s, NCH3), 4.70 and 4.75 (2H, 2 s, NCH2), 7.2–7.7 (3H, m, aromatics). Anal. calcd for C10H11Cl2NO: C, 51.74; H, 4.78; N, 6.03. Found: C, 51.70; H, 4.77; N, 6.04.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](=O)=[O:18]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: O=C(Cc1ccncc1)c1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(Br)cc1)c1ccncc1
Temperature: 135 °C
Yield: 47.5 %

Procedure:
A mixture of 200 mg (0.725 mmol) of l-(4-bromophenyl)-2-(4-pyridyl)-ethanone (from Step A) and 81 mg (0.725 mmol) of selenium(IV) oxide, and 5.5 mL of glacial acetic acid was heated to 135° C. for 2 h. After being cooled to room temperature, the reaction mixture was partitioned between saturated aqueous potassium carbonate and ethyl acetate. The aqueous layer was extracted twice more more with ethyl acetate. The organic layers were combined and washed with water and brine and dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure and the residue was flash chromatographed over silica gel (gradient elution 2-4% MeOH in DCM) to yield 100 mg of the titled compound, homogeous by TLC; mass spectrum (CI) m/e 290, 292 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][C:10](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[OH-].[OH-].[Pd+2].CO>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of the compound from step 3 (21.0 g, 71.7 mmol), Pd(OH)2 (3.0 g, 20% on C), methanol (500 ml) and 2 N HCl (37 ml) was hydrogenated on a Parr shake apparatus for 2 h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. Saturated K2CO3 solution was added (50 ml) and extracted with CH2Cl2 (2×250 ml). The combined extracts were washed with H2O (250 ml) and brine (100 ml), dried (Na2SO4) and evaporated to give the title-product as a pale yellow oil (19.3 g). δ (360 MHz, CDCl3) 2.58 (2H, d, J=7.3 Hz, CH2), 2.75-2.81 (3H, m, 2 of CH of CH2 and CH), 3.35-3.38 (2H, m, 2 of CH of CH2), 3.62 (3H, s, CO2Me), 4.31 (1H, s, CH), 7.14-7.18, 7.23-7.27 and 7.38-7.40 (total 10H, each m, Ar--H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][C:13]1([CH3:19])[O:18][CH2:17][CH2:16][NH:15][CH2:14]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:15]2[CH2:16][CH2:17][O:18][C:13]([CH3:19])([CH3:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC1(C)CNCCO1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (2.00 g, 8.43 mmol) in DMSO (10 mL) was added 2,2-dimethylmorpholine (commercially available from ChemBridge Corporation) (1.9 mL, 16.9 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil as 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=2.2 Hz), 3.87 (2H, m), 3.36 (4H, m), 1.26 (6H, s).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (324 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:13])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1c(Cl)cc(F)cc1C=O
Solvent: CCOCC
Product: COc1c(Cl)cc(F)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of 5-Fluoro-2-methoxy-3-chlorobenzaldehyde (2.0 g, 11.0 mmol) in dry diethyl ether (40 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in ether (8.8 mL, 27.12 mmol). The reaction mixture was brought to room temperature and was stirred for 30 min. then refluxed for 3 hours. It was then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-Fluoro-2-methoxy-3-chlorophenyl)ethanol (2.1 g, 98%): 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, 1H), 7.04 (dd, 1H), 5.19 (m, 1H), 3.84 (s, 3H), 2.18 (bs, 1H), 1.43 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:15][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[C:23]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[N:24][C:25]3[N:26]([N:28]=[CH:29][CH:30]=3)[CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1COCC1>C(O)(=O)C>[C:16]1([C:22]2[C:23]([C:31]3[CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[NH:15][C:10]6[CH:11]=[N:12][CH:13]=[CH:14][C:9]=6[N:8]=5)[CH2:5][CH2:6]4)=[CH:37][CH:38]=3)=[N:24][C:25]3[N:26]([N:28]=[CH:29][CH:30]=3)[CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Reactant: c1cc2nc(C3CCNCC3)[nH]c2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(-c2cn3nccc3nc2-c2ccc(CN3CCC(c4nc5ccncc5[nH]4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
252 mg (1.06 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine and 250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde were reacted as described in example 12.0. Additional NaBH(OAc)3 has been added after one, three and five hours (two equivalents each) and the reaction mixture has been stirred overnight at room temperature. Since the reaction has not been complete, 20 mL THF and 10 mL acetic acid were added. Another two equivalents of NaBH(OAc)3 were added. Because after one hour stirring at room temperature the reaction has not changed additional 126 mg 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine and another two equivalents of NaBH(OAc)3 were added. The reaction has been worked up after stirring at room temperature for 70 hours. After purification 28 mg of the desired material has been obtained.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:29]([O:30][CH3:31])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCNC(CCc2ccc(F)cc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Methyl 2-(4-fluorophenethyl)piperidine-4-carboxylate (3.89 g, 14.65 mmol) was dissolved in dichloromethane (150 mL). DIPEA (3.06 mL, 17.58 mmol) was added, followed by methyl carbonochloridate (1.615 mL, 20.51 mmol). The mixture was stirred at room temperature for 2 h. 0.1 HCl and DCM were added. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. Dimethyl 2-(4-fluorophenethyl)piperidine-1,4-dicarboxylate (3.19 g, 67%) was isolated. MS m/z 324 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24]O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][O:12][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: COc1ccccc1CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Yield: 54.6 %

Procedure:
A mixture of 3-(2-methoxyphenyl)propionic acid (5.0 g, 27.8 mmol), 2-(p-toluenesulfonyl)ethanol (5.5 g, 27.8 mmol), and p-toluenesulfonic acid hydrate (p-TsOH.H2O) (0.5 g) in 100 mL of toluene was refluxed with Dean-Stark trap for 5 h. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution (2×), dried over MgSO4, and concentrated to give 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 59, 5.5 g, 88%) as a light brown liquid.