Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:13]2[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:20]([O:22][CH2:23]C)=[O:21])CO)=[CH:6][CH:5]=1.O.C(OCC)(=O)C>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:23][O:22][C@@H:20]([OH:21])[CH:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[N:13]23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H]1CCCC(=O)N1[C@@H](CO)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCCC2[C@H](O)OCC(c3ccc(F)cc3)N12
Reaction time: 0.67 h
Yield: 73.6 %

Procedure:
Sodium borohydride (70.9 mg) was added to a solution of ethyl (R*)-1-[(R*)-1-(4-fluorophenyl)-2-hydroxyethyl]-6-oxopiperidine-2-carboxylate (290 mg) in methanol (5.0 mL) under ice-cooling, and the reaction solution was stirred for one hour and 40 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 183 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:22]=1[OH:23]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:16]2[C:7]=1[CH:8]1[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]2[CH:24]2[C:22]([C:21]([O:20][CH3:19])=[CH:27][C:26](=[O:28])[CH:25]12)=[O:23]
Reactant: COc1cc(O)ccc1O
Reactant: COc1ccc(OC)c2cc3ccccc3cc12
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2C3c4ccccc4C(c4c(OC)ccc(OC)c43)C2C1=O
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of 0.70 g (2.90 mmol) of 2 and 1.00 g (7.20 mmol) of 6 in 10 mL of toluene in a sealed tube was heated at 150° C. for 1 day, cooled to 25° C., concentrated to dryness, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate as solvent gave 0.52 g (48% yield) of compounds 5 as a mixture of exo- and endo-(1:1) isomers along with 0.62 g of 6. The exo- and endo-isomers were partially separated by silica gel column and the stereochemistry have not assigned. Compound 5, less polar isomer: MS, m/z 376 (M+), 375. 1H NMR d 7.24-7.18 (m, 2H), 7.08-7.04 (m, 2H), 6.65 (s, 2H, C6,7 Hs), 5.61 (s, 1H), 5.33 (bs, 2H), 3.82 (s, 6H, OMe), 3.48 (s, 3H, OMe), 3.12 (ABd, J=9 Hz, 1H), 3.06 (ABd, J=9 Hz, 1H). More polar isomer: MS, m/z 376 (M+), 375. 1H NMR d 7.40 (m, 2H), 7.16 (m, 2H), 6.60 (ABd, J=8.8 Hz, 1H), 6.56 (Abd, J=8.8 Hz, 1H), 5.65 (s, 1H, ═CH), 5.33 (bs, 2H, C9,10 Hs), 3.76 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.51 (s, 3H, OMe), 3.13 (Abd, J=9 Hz, 1H), 3.08 (Abd, J=9 Hz, 1H). This mixture of compounds was used in the next step.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=O)=[N:4][CH:3]=1.C([BH3-])#[N:21].[Na+].C([O-])(=O)C.[NH4+].C1COCC1>CCOC(C)=O.CO>[NH2:21][CH:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(N)c2ncc(Br)s2)CC1
Temperature: 80 °C

Procedure:
trans-Ethyl 4-(5-bromothiazole-2-carbonyl)cyclohexanecarboxylate (150 mg, 0.433 mmol), sodium cyanoborohydride (63 mg, 1.00 mmol), ammonium acetate (83 mg, 1.08 mmol), THF (0.6 mL), and methanol (1.8 mL) were combined in a sealed vial and heated to a temperature of 80° C. for 16 hours. The mixture was cooled to 23° C. and subsequently transferred to a separatory funnel containing EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to afford crude trans-ethyl 4-(amino(5-bromothiazol-2-yl)methyl)cyclohexanecarboxylate, which was used directly in the subsequent synthetic transformation without purification. MS ESI calc'd. For C13H20BrN2O2S [M+H]+ 347, 349. found 347, 349.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14](=O)[CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.N.[BH3-]C#[N:20].[Na+]>CCO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([CH:14]([NH2:20])[CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: CC(=O)C1(c2cnc(C)nc2)CCOCC1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(C2(C(C)N)CCOCC2)cn1
Yield: 33.5 %

Procedure:
A mixture of 1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone (300 mg, 1.35 mmol), saturated NH4OAc in EtOH (15 mL) and aq.NH3 (5 mL) was added NaCNBH3 (255 mg, 4.05 mmol) and heated to reflux overnight. The EtOH was removed. The residue was extracted with EtOAc (5×10 mL) and the organic layer was discarded. The precipitation of solid was collected by filtration from the aqueous layer after 16 hours to give 1-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanamine (100 mg, yield: 33.3%). 1H NMR (DMSO-d6 400 MHz): c58.67 (s, 2H), 3.80-3.65 (m, 2H), 3.20-3.05 (m, 2H), 2.63 (s, 3H), 2.45-2.35 (m, 1H), 2.35-2.25 (m, 2H), 1.81-1.70 (m, 2H), 0.87 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>[OH-].[Na+].O>[C:9]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccccc1C
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Ice (300 g) was added to o-cresol (21.6 g, 0.2 mol) dissolved in a solution of sodium hydroxide (12 g, 0.3 mol in water (100 ml). Acetic anhydride (30.6 g, 0.3 mol) was then added and the mixture was shaken for 1 min. The product was extracted into ether and then purified by reduced pressure distillation.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([N:19]([C@@H:16]2[CH2:17][CH2:18][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([OH:4])[CH2:6][CH2:7]3)=[O:12])[CH2:14][C@H:15]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH3:20])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(=O)O[C@H]1CC[C@H](C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCC(O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of the compound obtained in Example 518 (0.103 g) in methanol (1.8 mL) was added sodium carbonate (0.067 g) and the mixture was stirred at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (0.076 g, 80%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>COCCOCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccn3)CC2)cc1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of 1-chloro-4-nitro-benzene (4.34 g, 27.6 mmol) and anhydrous potassium carbonate (5.08 g, 36.8 mmol) was added to a solution of 1-(2-pyridyl)piperazine (3.0 g, 18.4 mmol) in diglyme (10 mL) and heated at reflux for 24 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the organic layer was washed with water (5×40 mL), brine (3×30 mL), dried over anhydrous sodium sulphate and concentrated to yield a crude compound. This was purified by washing with hexane (5×5 mL) and then pentane (2×5 mL) to afford 1-(4-nitrophenyl)-4-(2-pyridyl)piperazine (4.0 g, 77%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:15](=[O:24])[NH:16]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:25]/[C:26]2[NH:27][CH:28]=[CH:29][C:30]=2[O:31][CH3:32])/[C:15](=[O:24])[NH:16]3)=[CH:4][CH:3]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc(O)cc3)c21
Yield: 0 %

Procedure:
Using Method S above, 4-hydroxyphenyl boronic acid (85.0 mg, 0.62 mmol) (see Gilman, supra) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 6) using DPPFPdCl2 (17 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.42 mL, 0.84 mmol) and DME (15 mL) at reflux for 1 day to give (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (yield: 11 0 mg, 52%).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCCC1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-methoxycarbonylazetidine (28 g) in methanol (270 ml) and tetrahydrofuran (130 ml) was added 1N sodium hydroxide (115 ml) and the solution was stirred at room temperature for 1.5 hours. The solution was then concentrated to remove organic solvents under reduced pressure. The resultant aqueous solution was adjusted to pH 2.95 with 10% hydrochloric acid, and resulting precipitates were collected by filtration, washed with water and dried to give 1-(diphenylmethyl)-3-carboxyazetidine (24.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([C:17]#[N:18])(C)C.C(=O)(O)[O-].[Na+]>[I-].[Zn+2].[I-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][CH2:11][CH2:10][OH:9])[C:17]#[N:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: N#CC(OCCO)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Zinc iodide (50.6 mg) was added to a mixture of 2-(3-bromophenyl)-1,3-dioxolane (3 mL) and trimethylsilyl cyanide (2.49 mL), followed by stirring at room temperature for 1.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (elution solvent:heptane:ethyl acetate=7:3→1:1) to obtain 3.93 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29].N1CCCCC1>C(O)C>[CH3:16][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:24]1[NH:25][CH:26]=[C:20]2[C:21]=1[CH2:22][CH2:23][NH:18][C:19]2=[O:29])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[NH:15]C(=O)OC(C)(C)C)=[N:7][CH:8]=1.[ClH:25]>O1CCOCC1>[ClH:25].[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[NH2:15])=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-(2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)carbamate (1.0 g, 2.9 mmol) in 1,4-dioxane (5 ml) at 0° C. was added drop wise HCl in 1,4-dioxane (12%, 15.0 ml). The reaction was stirred at room temperature for 1 hour, then concentrated in vacuo. To this was then added DCM (50 ml) and a solution of sodium bicarbonate (aq, 7.5%, 15 ml). The organics were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (0-2% methanol/DCM) and then treated with HCl in 1,4-dioxane (12%, 5 ml), stirred for 2 hours, concentrated in vacuo, triturated with diethyl ether to afford the title compound as a single diastereomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][C:4]=1[CH3:12].Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([NH:11][CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)=[N:19][CH:18]=1)[CH3:21]
Reactant: CCc1cnc(Cl)nc1
Reactant: COc1ccc(CCN)cc1C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Yield: 51.4 %

Procedure:
Condensation of 2-(4-methoxy-3-methylphenyl)ethanamine (516 mg; 3.12 mmol) with 2-chloro-5-ethyl pyrimidine (446 mg; 3.12 mmol) as per general procedure E (1.5 eq DIEA, nBuOH, 130C, 20 hr) provided 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine (435 mg; 51% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([NH2:12])[CH:3]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cc(C)cc(N)c1O
Yield: 97.4 %

Procedure:
In 200 ml of ethanol was dissolved 4.0 g (20.5 mmol) of 2-hydroxy-5-methyl-3-nitroacetophenone, and the mixture was stirred at room temperature for about 2 hours in the presence of 1.0 g of 5% palladium carbon while bubbling hydrogen gas thereinto. The inorganic substance was filtered off, and the filtrate was concentrated to obtain 3.30 g (yield: 97%) of 3-amino-2-hydroxy-5-methylacetophenone as brown needle crystals.
Reaction SMILES: CN(C)CCN1C=C(C2C=CC(F)=C(C(F)(F)F)C=2)N=C1C1CCN(C2N=CN=C(N)C=2CC)CC1.[CH3:37][N:38]([CH3:75])[CH2:39][CH2:40][N:41]1[CH:45]=[C:44]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[C:48]([C:53]([F:56])([F:55])[F:54])[CH:47]=2)[N:43]=[C:42]1[CH:57]1[CH2:62][CH2:61][N:60]([C:63]2[N:68]=[CH:67][N:66]=[C:65]([NH2:69])[C:64]=2/[CH:70]=[CH:71]/[O:72][CH2:73][CH3:74])[CH2:59][CH2:58]1>>[CH3:75][N:38]([CH3:37])[CH2:39][CH2:40][N:41]1[CH:45]=[C:44]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[C:48]([C:53]([F:55])([F:56])[F:54])[CH:47]=2)[N:43]=[C:42]1[CH:57]1[CH2:58][CH2:59][N:60]([C:63]2[N:68]=[CH:67][N:66]=[C:65]([NH2:69])[C:64]=2[CH2:70][CH2:71][O:72][CH2:73][CH3:74])[CH2:61][CH2:62]1
Reactant: CCO/C=C/c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Agent: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Product: CCOCCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine using (E)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2-ethoxyvinyl)pyrimidin-4-amine. LC-MS: (M+1=550, obsd.=550).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a suspension of 2-amino-4-chlorophenol (1.43 g, 10.0 mmol) in methanol was added acetic anhydride (0.945 mL, 10.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo to give the subtitled compound (1.5 g).
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10]1
Reactant: c1ccc(CC2CCCNC2)cc1
Reactant: COC(=O)CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCN1CCCC(Cc2ccccc2)C1
Temperature: 110 °C
Yield: 64.7 %

Procedure:
To a solution of 3-benzylpiperidine hydrochloride (2 g, 9.4 mmol) in DMF (40 mL) were added methyl 5-bromovalerate (1.6 mL, 11.3 mmol) and potassium carbonate (3.2 g, 23.6 mmol). This heterogeneous mixture was heated at 110° C. for 1 hr then cooled at 25° C., diluted with water (200 mL) and diethyl ether (200 mL). The aqueous solution was extracted with diethyl ether (100 mL) and the collected organic phase was washed with brine (200 mL), dried and concentrated in vacuum. The crude compound was purified by silica gel column chromatography using CH2Cl2/MeOH as eluant to afford the title compound as an oil (1.76 g, 65%). 1H-NMR (CDCl3): 0.8-1.0 (m, 1H); 1.4-1.7 (m, 8H); 1.8-1.95 (m, 2H); 2.25-2.35 (m, 4H); 2.4-2.6 (m, 2H); 2.75-2.9 (m, 2H); 3.65 (8, 3H); 7.132 (d, J=7.0, 2H); 7.186 (d, J=7.2, 11); 7.264 (t, J=7.2, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C.[I-].[Na+]>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of 1.8 g of 4-diphenylmethylpiperidine, 1.92 g of N-(3-bromopropyl)phthalimide, 3.0 g of sodium carbonate and 20 mg of sodium iodide in 70 ml of methyl isobutyl ketone was heated under reflux for 5 hours. At the end of this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.0 g (yield 95%) of the title compound as crystals, melting at 104°-106° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:30]=[N+:31]=[N-:32])[C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 110 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,3S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g, 2.35 mmol) and NaN3 (0.370 g, 5.67 mmol) in dry DMF (12 mL) was stirred at 110° C. for 60 h. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×), the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4 to 1:2) to afford the title compound as a colorless foam. MS (LC-MS): 398 [M+H]+, 342 [MH−tBu]+, 298 [MH−Boc]+; tR (HPLC conditions c): 5.15 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O:25][C:26](=O)/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36])OC(C)(C)C.[Cl-].[NH4+]>O1CCCC1.COC(C)(C)C.C1CCCCC1.O>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:26](=[O:25])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)OC(=O)/C=C/c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: C1CCCCC1
Product: O=C(/C=C/c1ccc(F)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (2.5M in hexanes) (100 mL, 250 mmol) was added dropwise to a stirred solution of (S)-(−)-4-benzyl-2-oxazolidinone (43.55 g, 250 mmol) in anhydrous tetrahydrofuran (350 mL) at 0° C. The resulting solution was cooled to −78° C. for 30 minutes and added dropwise to a stirring solution of tert-butyl (2E)-3-(2,4-difluorophenyl)prop-2-enoyl carbonate, from preparation 27 via cannula at −78° C. The resulting suspension was allowed to warm to 0° C. and saturated ammonium chloride solution (75 mL) was added, followed by water (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give a slurry. Cyclohexane (178.5 mL) and tert-butyl methyl ether (126 mL) were added to the slurry and the mixture was stirred for 2 hours at room temperature. The resulting white solid was collected via filtration and dried in a vacuum oven at 40° C. to give the desired product, 45.48 g (61%).