Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1.[OH-].[Na+]>C(O)(C)C>[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc[nH+]cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: C(=Cc1ccncc1)c1ccccc1
Reaction time: 2 h

Procedure:
To 67.5 parts of the 4-picolinium quaternary salt as in Example 13 but without the acid salt was added 100 parts isopropanol, 32.5 parts benzaldehyde, and one part piperidine. The resulting solution was boiled at reflux two hours, 100 parts 40% sodium hydroxide added, and the heating continued for two hours. The cooled mixture was extracted with chloroform, and the organic phase evaporated to dryness to yield a residue that was recrystallized from methanol-water to give 21 parts 4-styrylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Br:1])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1ccccc1Br)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Br)CC1
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (45.66 g, 148.9 mmol) in THF was added slowly to a mixture of NaH (7.14 g of a 60% mineral oil dispersion, 178.5 mmol) in THF (200 ml) and the mixture was stirred for 1 hr. A solution of 1-(tert-butoxycarbonyl)-4-piperidinone (29.67 g, 148.9 mmol) in THF was added dropwise and the mixture was heated to reflux for 1.5 hr. The mixture was cooled and quenched with brine. The mixture was diluted with ethyl acetate, washed with water, and dried with brine. The organic layer was concentrated in vacuo to an oil. The oil was dissolved in acetonitrile and extracted with hexane. The acetonitrile layer was concentrated in vacuo to give 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]piperidine (XI) as an oil that solidified upon standing (48.3 g, 97%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17](OS(C)(=O)=O)[C:18]([F:21])([F:20])[F:19])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH2:17][C:18]([F:21])([F:19])[F:20]
Reactant: [H][H]
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(OS(C)(=O)=O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc(=O)c(O)c1CC(F)(F)F
Yield: 9.7 %

Procedure:
A mixture of methanesulfonic acid 1-(3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (2.80 g, 7.15 mmol) and 10% Pd/C (0.56 g) in ethyl alcohol was subjected to hydrogenation in a Parr apparatus under 50 psi hydrogen pressure for 90 min. The mixture was filtered through a pad of CELITE™, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of isopropyl alcohol and a conc. NH4OH solution (90/10, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness, thereby affording 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (first crop: 143 mg, 9.7% yield, second crop: 240 mg, 16.2% yield). 1H NMR (90 MHz, CD3OD) δ (ppm): 7.66 (d, J=7.2 Hz, 1H), 6.41 (d, J=7.4 Hz, 1H), 3.89 (q, J=10.2 Hz, 1H) and 3.82 (s, 3H); MS-ESI (m/z): 208 [M+1]+, 188.2, 168.2. HPLC purity (peak area percent) of both fractions are about 98% at λ=254 nm, RT=3.75 min (HPLC method is described in Part A above).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[NH2:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])=[O:6]
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Cl)n1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
2-Chloro-6-methylnicotinic acid (500 mg, 2.9 mmol) was suspended in CH2Cl2 (14.6 mL). Oxalyl chloride (0.3 mL, 3.5 mmol) was added followed by 3 drops of DMF and the reaction was stirred at 23° C. for 2 h. The solvent was removed by rotary evaporation and the residue was dried under vacuum. The crude acid chloride was dissolved in CH3CN (14 mL) and 2,4-difluorobenzenamine (0.33 mL, 3.2 mmol) was added followed by triethylamine (0.41 mL, 2.9 mmol). The reaction was stirred at 23° C. for 16 h and then concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and sat. aq. NaHCO3 soln (30 mL). A little water was added to help break up some of the residual salts. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. Trituration with hot 5% EtOAc-hexanes afforded the desired product as a light tan powder (559 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H), 6.82-7.09 (m, 2H), 7.22-7.32 (d, 1H, J=7.63 Hz), 8.18 (d, 1H, J=8.14 Hz), 8.28-8.50 (m, 1H), 8.57 (s, 1H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](O)(=[O:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[C:37]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16]1)(=[O:39])[CH3:38]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (8.4 μl) was added, acetic acid (6.9 μl) and WSC.HCl (23 mg) were added thereto and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cc(F)cc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cc(F)cc(Cl)c2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A mixture of tert-butyl 3-(3-chloro-5-fluorophenyl)-3-hydroxyazetidine-1-carboxylate (1.25 g, 4.14 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (50 ml) was stirred at ambient temperature for 1 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.74 g). MS m/z (rel. intensity, 70 eV) 201 (M+, 1), 172 (47), 157 (53), 130 (76), 109 (bp).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1
Yield: 50.8 %

Procedure:
A solution of 0.90 g (6.61 mmol) of 4'-hydroxyacetophenone, and 1.93 g (9.92 mmol) of ethyl 4-bromobutyrate in 1.80 mL of N,N-dimethylformamide is stirred for 48 hours, under dry conditions with 2.74 g (19.8 mmol) of potassium carbonate and 0.110 g (0.66 mmol) of potassium iodide. The reaction mixture is then evaporated under vacuum, and the residue partitioned between ether and water. The organic phase is separated, washed thrice with water, dried with magnesium sulfate, filtered, and evaporated under vacuum to give a brown solid. This is recrystallized from a warm ether-hexane mixture. The beige crystals are air dried, leaving 0.84 g (51%) of 4-(4-acetylphenoxy)butanoic acid, ethyl ester: m.p. 59°-61° C.; IR (KBr) 1740, 1670 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 251.1285 Δ=-0.2 mmμ (M+ +H). Analysis calculated for C14 H18O4 : C, 67.18; H, 7.25; O, 25.57. Found: C, 67.16; H, 7.16; O, 25.68.
Reaction SMILES: [N+]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=C[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[N:13]([O-])=O.[Na+].Cl>O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][CH:12]=2)[CH:8]=[N:13]1
Reactant: O=N[O-]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc2[nH]ncc2c1
Reaction time: 2.5 h
Yield: 154.3 %

Procedure:
6-Nitroindole (AA1, 1.0 g, 6.2 mmol) was suspended in a solution of sodium nitrite (4.3 g, 62 mmol) in H2O (123 mL). To the suspension 6N HCl was added slowly until the pH was about pH 1. The resulting mixture was stirred at about rt, with protection from light, for about 2.5 h and extracted with EtOAc (120 mL×3). The combined extracts were washed with H2O (50 mL), brine (50 mL), dried (Na2SO4) and evaporated to give 1.13 g of indazole AA2 as a yellow-pink solid. A solution of AA2 (450 mg, 2.4 mmol) and pyrrolidine (836 mg, 11.8 mmol) in ClCH2CH2Cl:DMF:HOAc (90:9:1) were stirred at about rt for about 20 min, to which was then added NaB(OAc)3H (1.25 g, 5.9 mmol) in one portion. The mixture was stirred at about rt for about 1 h, and then diluted with EtOAc (200 mL), washed with saturated NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and evaporated to afford 570 mg of AA3 as a viscous brown solid. 6-Nitroindazole AA3 (4.4 g, 17.8 mmol) was dissolved in dry THF (200 mL) under argon and 2,6-dichlorobenzyl bromide (4.3 g, 17.8 mmol) was added, followed by portionwise addition of pulverized KOH (1.17 g, 17.8 mmol) over about the next 20 min. The reaction was stirred at about rt for about 1 h and then evaporated in vacuo to an oil, which was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was separated and washed twice with water, three times with brine, dried (Na2SO4) and evaporated in vacuo to a brown solid. This was purified by flash column chromatography using DCM:MeOH (19:1) to afford 2.4 g of a tan solid which was combined with ferric chloride hexahydrate (0.30 g, 1.1 mmol) and activated charcoal (3.0 g, 0.25 mmol) in MeOH (200 mL). Dimethyl hydrazine (32 g, 0.53 mmol) was added and the reaction was refluxed for about 2 h, cooled to about rt and filtered through dicalite, which was washed several times with DCM:MeOH (4:1). The combined filtrates were evaporated in vacuo to a brown solid, which was purified by flash chromatography with DCM:MeOH:NH4OH (90:8:1) to give 1.75 g of amine AA4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Cl.[CH3:10][NH:11][CH3:12].[CH2:13]=O.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][CH2:10][N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: C=O
Reactant: Cc1cncc(C)n1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cncc(CCN(C)C)n1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A mixture of 2,6-dimethylpyrazine (Pyrazine Specialities, Inc., Atlanta, Georgia, containing 2%, 2,5-isomer) (15.5 g) and dimethylamine hydrochloride (13.0 g) was heated until it began refluxing, and then formaldehyde (22.5 g as 38% aqueous solution) was added over a 30-min period. The resulting solution was refluxed for 2 hours. The solution was cooled to room temperature and diluted with water, made basic by the addition of 10% aqueous solution of sodium hydroxide, and extracted with chloroform. After removing the solvent, distillation of the residue gave 7.8 g of 2-methyl-6-dimethylaminoethylpyrazine with 5% of the 2,5-isomer (33% yield), 120°-126° C./12 mm Hg.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].CC(O)C.B.C(N)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[CH:19]=[C:20]([NH2:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[S:1](=[O:3])(=[O:2])([OH:5])[OH:4].[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH:20]([NH2:26])[CH2:19][C:18]([O:17][CH3:16])=[O:27]
Reactant: COC(=O)C=C(N)CC(=O)OC
Agent: B
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)(C)N
Solvent: C1CCOC1
Product: COC(=O)CC(N)CC(=O)OC
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A diluted alcoholic sulfuric acid solution is prepared by adding sulfuric acid (20.69 Kg) to i-PrOH (51.7 Kg) at 0-5° C. The resulting solution was slowly added to a solution of tert-butylamine borane (9.19 Kg) in THF (69.3 Kg), maintaining the temperature below −5° C. Dimethyl-3-aminoglutaconate (18.28 Kg) was slowly added to the resulting mixture, maintaining the temperature below 0° C. The resulting reaction mixture was stirred between 0° C. and 15° C. overnight, then quenched by slow addition to water (166 Kg) while maintaining the temperature below 10° C. and the pH between 5 and 7 by adding concentrated aqueous NaOH. The pH of the mixture was then adjusted to about 9-10 by adding concentrated aqueous NaOH at the end of the quenching process. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine (20.6 Kg), filtered through a cotton cartridge and concentrated under reduced pressure to give 3-amino-pentanedioic acid dimethyl ester (17.87 Kg, 97% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:9]=2)[CH2:4][CH2:3]1.[C-:31]#[N:32].[K+].[OH2:34]>CC#N>[C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[N:9]=[C:8]([N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:31]([NH2:32])=[O:34])[CH2:3][CH2:4]4)[C:13]([F:14])=[CH:12][N:11]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:30])[CH3:29]
Reactant: O
Reactant: [C-]#N
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(N)=O)CC4)n3)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (48 mg, 0.12 mmol) in CH3CN (2 mL), a solution of KCN (60 mg, 0.74 mmol) in H2O (2 mL) was added. The suspension became clear. The mixture was stirred at 70° C. for 2 h. It was then purified by HPLC to give the titled compound (12 mg). MS 457.3 (M+H); UV 204.8, 266.8 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:24])[CH:21]=[CH:22][CH3:23])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: C/C=C/C(=O)Cl
Solvent: C1CCOC1
Product: CC=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.2 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4(3-bromoanilino)-quinazoline (J Med Chem, 1985:3482) in 5 mL of tetrahydrofuran was added dropwise a solution of 0.105 g of crotonic acid chloride in 5 mL of tetrahydrofuran. When the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 15 hours. The reaction was filtered to remove the yellow solid which was washed with tetrahydrofuran and recrystallized from 20 mL of boiling methanol to afford 0.060 g of the desired product, mp >250° C.
Reaction SMILES: [CH3:1][Li].[CH2:3]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>CCOCC>[CH2:3]([CH:10]1[C:15]([OH:16])([CH3:1])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCN1CCCC(=O)C1CCCCCCC
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCN1CCCC(C)(O)C1CCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl lithium (7 ml, 2 M solution in ether) was injected, under nitrogen, into a stirred solution of 2-n-heptyl-1-n-octylpiperidin-3-one (3.4 g) in dry ether (100 ml) at -78°. The mixture was allowed to warm gradually to room temperature. After 3 hours, thin layer chromatography indicated that some starting material remained. The solution was cooled to -78° and methyl lithium (3 ml, 2 M solution in ether) was injected. The mixture was allowed to warm gradually to room temperature and was allowed to stand for 2 days. Water (10 ml) was added dropwise and the ether phase was separated, dried over magnesium sulphate and evaporated in vacuo. The product was purified by column chromatography to give 2-n-heptyl-3-hydroxy-3-methyl-1-n-octylpiperidine as a yellow gum (1.47 g, 41% yield).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:17]3)=[O:15])=[C:8]([CH3:10])[N:9]=2)[CH2:2]1.C=O.[BH3-][C:35]#N.[Na+]>O1CCCC1>[CH3:31][C:30]1[CH:29]=[CH:28][C:13]([C:14]([N:16]2[CH2:17][CH:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH2:19]2)=[O:15])=[CH:12][C:11]=1[C:7]1[NH:6][C:5]([CH:3]2[CH2:4][N:1]([CH3:35])[CH2:2]2)=[N:9][C:8]=1[CH3:10]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CNC2)nc1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CN(C)C2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 189.2, 50 mg, 0.12 mmol) in tetrahydrofuran (1 mL). Formaldehyde (65 μL, 37% wt, 0.57 mmol) and NaBH3CN (30 mg, 0.48 mmol) were added to the reaction. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was extracted with 3×3 mL of ethyl acetate and the combined organic extracts were washed with 3×1 mL of brine and concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.03% NH3H2O and MeCN (26.0% MeCN up to 40.0% in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 1.8 mg (3%) of the title compound as a white solid. m/z (ES+) 426 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O[C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][CH:31]2[CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][CH:31]2[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=2)=[CH:27][CH:26]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc(CC2CCc3ccc(O)cc32)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC2CCc3ccc(OS(=O)(=O)C(F)(F)F)cc32)cc1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.08 mL, 0.48 mmol) was dropwise to a solution of toluene (2 mL) and aqueous 30% K3PO4 (2 mL) containing the intermediate from Step D (63 mg, 0.22 mol). The solution was stirred at room temperature until no starting material remained by HPLC analysis. The solution was partitioned between ethyl acetate and water. The organic phase was washed with water and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J=8.2 Hz, 2H); 7.27 (d, J=8.1 Hz, 2H); 7.08 (dd, J=2.3, 8.2 Hz, 1H); 6.95 (d, J=2.1 Hz, 1H); 3.95 (s, 3H); 3.56-3.50 (m, 1H); 3.15 (dd, J=6.2, 13.5 Hz, 1H); 2.92-2.80 (m, 3H); 2.28-2.20 (m, 1H); 1.90-1.83 (m, 1H). LCMS2 2.71 min. (M+H)=415
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: Nc1nnn[nH]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Nc3nnn[nH]3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 5-amino-1H-tetrazole (204.6 mg; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (550 mg; 64%).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:27][C:28]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:29]=1[CH2:30][OH:31]>>[ClH:1].[CH3:10][C@H:9]1[CH2:8][NH:7][CH2:6][C@@H:5]([CH3:18])[N:4]1[C:2]([O:31][CH2:30][C:29]1[CH:32]=[C:33]([O:36][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:34]=[CH:35][C:28]=1[F:27])=[O:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1cc(O)ccc1F
Reactant: ClCc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2ccccc2)ccc1F
Product: Cl

Procedure:
5-Benzyloxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine, benzyl chloride and 2-fluoro-5-hydroxybenzyl alcohol according to the methods described for Examples 52, 54 and 96 to give the product as a white solid (0.229 g, 56% overall); (Found; C, 61.5; H, 6.5; N, 6.8%. C21H25FN2O3.HCl requires C, 61.7; H, 6.4; N, 6.85%); δH (400 MHz, DMSO-d6) 9.86 (1H, br), 9.17 (1H, br), 7.45–7.33 (5H, m), 7.17 (1H, t, J 9 Hz), 7.08 (1H, m, J 2.8 Hz), 7.02 (1H, m), 5.12 (2H, s), 5.09 (2H, s), 4.29 (2H, m), 3.15 (2H, d, J 12.8 Hz), 3.06 (2H, dd, J 4.8 and 12.8 Hz), and 1.29 (6H, d, J 7.2 Hz).