Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])OC1)=O)(C)(C)C.Br[CH2:22][Cl:23].C([Li])CCC.Cl>CCCCCC.O1CCCC1>[ClH:23].[NH2:8][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11](=[O:20])[CH2:22][Cl:23]
Reactant: ClCBr
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (1.00 g) and bromochloromethane (0.31 ml) were added to dehydrated tetrahydrofuran (36 ml). After cooling to −78° C., 1.53 M solution (3.07 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 40 minutes. 6 N Hydrochloric acid was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. The reaction mixture was concentrated to a half volume, stirred at 50° C. for 1 hour and cooled to room temperature. After the addition of isopropyl acetate followed by the extraction with water twice, the obtained aqueous solution was analyzed by HPLC to find that intended (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.65 g) was obtained in a yield of 77% According to HPLC analysis with an optically active column, the optical purity of (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride thus obtained was confirmed to be >99% e.e.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To an ice-cooled solution of 2-bromo-1-(2,5-dichlorophenyl)ethanone (0.10 g, 0.37 mmol) in N,N-dimethylformamide (8 mL) was added potassium phthalimide (76 mg, 0.41 mmol). The mixture was warmed to room temperature for 2 hours. The resultant mixture was then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization with diethyl ether afforded 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione as a white solid. (110 mg, 88% yield). 1H NMR (400 MHz, CDCl3): 7.92-7.94 (m, 2H), 7.78-7.80 (m, 2H), 7.72 (m, 1H), 7.45-7.46 (m, 2H), 5.08 (s, 2H).
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[C:25]([O:27][CH3:28])=[O:26])=[O:17])[CH:7]=[CH:8][CH:9]=1>CC#N.C(Cl)Cl>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([N:18]2[CH2:23][CH:22]([O:24][CH3:1])[CH2:21][CH2:20][CH:19]2[C:25]([O:27][CH3:28])=[O:26])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCC(O)CN1C(=O)c1nc(C)sc1-c1cccc(F)c1
Reactant: CI
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1CCC(OC)CN1C(=O)c1nc(C)sc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
MeI (6.8 mmol, 0.43 mL) was added to a mixture of methyl 1-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-hydroxypiperidine-2-carboxylate (0.68 mmol, 0.26 g) and Ag2O (3.4 mmol, 0.8 g) in CH3CN (3 mL) at rt. The resulting mixture was stirred at rt for two days. The reaction mixture was diluted with DCM and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to give desired product methyl 1-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidine-2-carboxylate which was used for next step without further purification (Y: 96%).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:14])=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>O.C1COCC1>[C:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=1[O:14][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C=O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(=S)N(C)C)c(C(C)(C)C)cc1C=O
Temperature: 18.5 °C
Reaction time: 1.17 h

Procedure:
To a solution of 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (33.7 Kg, 162 mol correcting for a GC purity of 92.5%) in water (60 L) and THF (45 L) under a nitrogen atmosphere was added potassium hydroxide (5.0 Kg of a 45% aqueous solution) to adjust the pH of the solution to pH 12. The resulting solution was stirred at 10-19° C. while a solution of dimethylthiocarbamoyl chloride (28.7 Kg) in THF (36 L) was added over a 2.5 hour period with simultaneous addition of 45% KOH (22.2 Kg) in order to hold the pH of the reaction mixture between 11.8 and 12.1. The vessel containing the dimethylthiocarbamoyl-THF solution was rinsed with THF (5 L) and the rinse combined with the whole. Additional 45% KOH (3.8 Kg) was added to the mixture over a 2 hour period at 15-19° C. in order to maintain a basic pH in the range 11.7-11.8. Stirring at 18-19° C. was continued for another 70 minutes. Ethyl acetate (45 Kg) and heptane (34 Kg) were added to the reaction mixture. Phase separation was assisted by the addition of NaCl (22 Kg) in water (60 L). After separation the aqueous layer was extracted with a solution of ethyl acetate (23 Kg) and heptane (17 Kg). The combined organic layers were diluted with ethyl acetate (50 Kg) and extracted with 10% KOH (2×35 L) followed by 10% aqueous sodium chloride solution (2×33 Kg). The organic product solution was concentrated to a volume of approximately 45 L. This was treated with 45% KOH (50 gm) and diluted with methanol (40 L) and the resulting solution cooled to 43° C. Water (7 L) was added over 15 to 30 minutes while maintaining the temperature between 40 and 45° C. The solution was cooled slowly with addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester seed crystals. Crystallization began at 40° C. The mixture was stirred and cooled over several hours to 2° C. The mixture was filtered and the solid washed with a solution of methanol (25 L) and water (6 L) followed by water (20 L) and vacuum dried at 40-45° C. overnight until the water content was 0.03%. This gave dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester (3a): 34.8 Kg (125 mol, 77%): mp: 79.5-81° C.; Assay (HPLC): 100.0 area %; ROI: 0.03%.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH3:34])[CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:33][C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=3[CH3:34])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: COc1cc(C)c(N)cn1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cnc(OC)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 10 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 6-methoxy-4-methylpyridin-3-amine (1.10 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (487 mg, 2.83 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was irradiated by microwave at 180° C. for 10 min. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give an amorphous which was recrystallized from ethyl acetate/n-hexane to give the title compound (190 mg, 0.402 mmol, 10%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[N:16]3[CH2:32][C:33]([F:36])([F:35])[F:34])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 93.6 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.146 mmol), lithium (bis-trimethylsilyl)amide (49 mg, 0.292 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.2 mL, 0.876 mmol) was prepared ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (58 mg, 95% yield) as a yellow oil. 1H NMR (CDCl3) δ 8.54 (s, 1 H), 7.37 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.97 (m, 2 H), 4.83 (m, 2 H), 4.49 (m, 2 H), 4.13 (s, 2 H), 1.46 (m, 3 H); MS m/z 425 M+1).
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.C(OC1(C#CCBr)CCCCCCC1)(=O)C.C([O:34][C:35]1([C:43]#[C:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57]CC)=[O:56])[C:47]#[N:48])CC[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)(=O)C>>[OH:34][C@H:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:43]#[C:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56])[C:47]#[N:48].[OH:34][C@H:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:43]#[C:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56])[C:47]([NH2:48])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCOC(=O)CCCCCCN(C#N)CC#CC1(OC(C)=O)CCCCCCC1
Agent: CC(=O)OC1(C#CCBr)CCCCCCC1
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by a equimolar amount of -1-acetoxy-1-(3-bromo-1-propynyl)cyclooctane (Example Q). The product of Step A is thus ethyl 7-{N-[3-(1-acetoxycyclooctyl)-2-propyn-1-yl]cyanamido}heptanoate. The subsequent steps yield 7-{N-[3-(1-hydroxycyclooctyl)-2-propyn-1-yl]cyanamido}heptanoic acid (B) and 7-{1-[3-(1-hydroxycyclooctyl)-2-propyn-1-yl]ureido}heptanoic acid (C).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].OC1C=CC(CO)=CC=1>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]
Reactant: OCc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: OCc1ccc(O)cc1
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 85 %

Procedure:
The procedure from Example 6, part A was used except 2-(chloromethyl)quinoline was substituted for 7chloro-(2-chloromethyl)quinoline and 3-hydroxybenzyl alcohol was substituted for 4-hydroxybenzyl alcohol. The intermediate was obtained in 85% yield: mp 82°-86° C.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (71 mg, 0.18 mmol) in methylene chloride (1.2 mL) was added 4.0 M hydrogen chloride in dioxane (0.35 mL, 1.4 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed to give the desired product as white solid (60 mg, 100%). LCMS calculated for C15H19N4OS (M+H)+: m/z=303.1. Found: 303.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51]2[N:56]=[CH:55][C:54]([NH2:57])=[CH:53][N:52]=2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:57][C:54]1[CH:53]=[N:52][C:51]([NH:50][C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=2)=[N:56][CH:55]=1)=[O:6]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(Nc2ncc(N)cn2)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(NC(=O)c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-(3-trifluoromethyl-benzoylamino)-benzoic acid (0.524 g, 1.53 mmol, 1.1 equiv) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.305 g, 1.74 mmol, 1.25 equiv) and diluted with DCM (10 mL). This was immediately treated with 4-methyl morpholine (0.458 mL, 4.16 mmol, 3 equiv) and allowed to stir at ambient temperature for 1 hour. Intermediate 68 (0.3 g, 1.38 mmol, 1 equiv) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were purified via silica gel chromatography. Eluting with 1:1 EtOAc in Hexanes afforded desired product. Beige solids (0.19 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:5][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:6]1[S:5][C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:8]2=[O:23])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)n1
Solvent: CC#N
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.40 g, 4.10 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (0.73 g, 4.10 mmol). The reaction mixture was stirred at 0° C. for 1 h, quenched with 10% sodium thiosulfate solution (10 mL), diluted with ethyl acetate (200 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 69% yield (1.20 g): mp 107-108° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 4.51 (s, 2H), 4.08-3.99 (m, 2H), 3.47-3.41 (m, 2H), 2.25 (s, 3H); MS (ES+) m/z 420.1 (M+1), 422.1 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=CN=C1.[Na].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C.[CH3:16][N:17]([CH:19]=O)[CH3:18]>>[BrH:7].[Br:7][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][N:17]1[CH:19]=[CH:5][N:1]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CN(C)C=O
Reactant: C=CCCCCCCBr
Agent: [Na]
Product: Br
Product: CCCCCCC(Br)Cn1ccnc1
Reaction time: 4 h

Procedure:
Combine sodium imidazole (5 g) and 8-bromo-1-octene (5 g) in DMF and stir overnight. Partition the reaction product between water and dichloromethane, evaporate the organic layer and purify the resultant residue on a silica gel column. Add the imidazole compound (4.6 g) and phenol (1 g) to dichloromethane (250 ml), saturate the solution with HBr gas and stir for 4 hours. Evaporate the solvent and wash the residue with THF: hexane (1:1) to obtain 1-(2-bromooctyl)imidazole hydrobromide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][N:16]([CH2:29][CH2:30][C@@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[CH2:33])[C:12]=2[N:13]=[CH:14][N:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([Br:1])[N:16]([CH2:29][CH2:30][C@@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[CH2:33])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: C=C[C@@H](CCn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@@H](CCn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Yield: 83.3 %

Procedure:
A solution of N-bromosuccinimide (1.35 g) in THF (23 ml) was added to a solution of (R)-tert-butyl (5-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-1-en-3-yl)carbamate (3.21 g) obtained in Step 6 in THF (26 ml) under ice-cooling over 30 minutes. The mixture was stirred under ice-cooling for 30 minutes. After adding a 5% aqueous sodium thiosulfate solution, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound as a light-brown solid (3.15 g).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25]O)([CH3:24])([CH3:23])C.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>[Mo](=O)(=O)=O>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:44]([O:18][N:13]2[C:12]([CH3:20])([CH3:19])[CH2:11][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][C:14]2([CH3:16])[CH3:17])([O:18][N:13]2[C:14]([CH3:16])([CH3:15])[CH2:24][CH:21]([O:25][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:23][C:12]2([CH3:19])[CH3:11])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCC
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Product: CCCCCCCCCCCCCCCCCC(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
A mixture of 80 mmol of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 250 mmol of 90% tert-butyl hydroperoxide, 125 grams of octadecane and 5 mmol of molybdenum trioxide is heated ait 140° C. in a Fischer-Porter prerssure bottle till the red color of the N-oxyl compound is no longer visible. The reaction mixture is purified by flash chromatography.
Reaction SMILES: [O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C)C=O.C(O)(=O)C>[O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9]([O:14][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 24.5 %

Procedure:
4.4 g (15.4 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (compound 1.1) [sic] are dissolved in 40 ml of dimethylformamide, and 0.46 g (18.4 mmol) of sodium hydride is added. The mixture is stirred for 1 hour and then 3.4 g (15.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. The mixture is stirred at room temperature for 24 hours and then cautiously hydrolyzed with 10 ml of water, the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 ml of ethyl acetate, washed with water, dried over sodium sulfate and distilled to remove solvents. 10 ml of methyl t-butyl ether are added to the residue, and the precipitate is filtered off with suction. Drying results in 1.6 g of a white powder.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:7]3[N:8]=2)=[CH:15][CH:16]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Product: COc1ccc(-c2nn3c(N4CCCC4)cccc3c2C(C)=O)cc1
Yield: 84 %

Procedure:
In a similar manner as described in Example 1 from 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (5.00 g, 16.6 mmol) and pyrrolidine, 1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (4.68 g, 84%) was obtained as a yellow crystalline solid. 1H NMR (CDCl3): δ 7.79 (d, 1H), 7.50 (dd, 2H), 7.33 (t, 1H), 6.97 (dd, 2H), 6.12 (d, 1H), 3.84 (s, 3H), 3.74–3.70 (m, 4H), 2.11 (s, 3H), 1.99–1.95 (m, 4H); MS m/z 336 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2([CH2:20][CH2:21][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:18][CH:17]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)cc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound: Rf =0.36 (silica gel, 6% methanol/dichloromethane).