Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH:14]=[N:15]O)=[CH:10][CH:9]=[CH:8][CH:7]=3.[ClH:17]>>[ClH:17].[ClH:17].[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][NH2:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ON=Cc1cn2c(ccc3ccccc32)n1
Agent: Cl
Product: NCc1cn2c(ccc3ccccc32)n1
Reaction time: 4 h

Procedure:
A solution of 1.0 g of imidazo-[1,2-a]-quinoline-2-carboxaldehye oxime in 100 ml of 0.25N methanolic hydrogen chloride in the presence of 0.100 g of 10% palladized carbon was hydrogenated at atmosphere pressure for 4 hours and after 175 ml of hydrogen were absorbed, 0.200 g of additional catalyst were added thereto. The mixture was hydrogenated further at 50° C. under atmosphere pressure for 2 hours during which 62 ml of hydrogen were absorbed. The mixture was filtered through cellulose powder and the filtrate was concentrated under reduced pressure. Anhydrous ether was added to the concentrate which was then cooled in ice to induce crystallization. The mixture was filtered and the recovered product was dried at 50° C. under vacuo and was crystallization from a methanol-ether mixture to obtain 0.85 g of imidazo-[1,2-a]-quinoline-2-methanamine dihydrochloride in the form of hygroscopic colorless crystals melting at 320°-325° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8](=O)[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+].[NH3:17]>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([NH2:17])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: N
Reactant: COCC(=O)COc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COCC(N)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Dissolve 1-(4-fluorophenoxy)-3-methoxy-propan-2-one (860 mg) in ammonia (7N in MeOH, 14.5 mL) and add molecular sieves (1 g). Stir the mixture at ambient temperature overnight. Cool the reaction to 0° C.; add sodium tetrahydroborate (0.66 g, 17.36 mmol); and stir the mixture at ambient temperature for 2 hours. Filter the mixture through a Celite® plug and rinse with MeOH. Concentrate the collected filtrate; dissolve in DCM; and wash with saturated aqueous NaHCO3 solution. Concentrate the filtrate under reduced pressure. Purify the mixture via SCX column, eluting with 7N NH3/MeOH to give the title compound (680 mg, 78.6%). MS (m/z): 200 (M+1).
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].Cl[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1>COCCOC>[CH:13]([C:9]1[CH:8]=[C:7]([Sn:2]([CH3:4])([CH3:3])[CH3:1])[CH:12]=[CH:11][N:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(Cl)ccn1
Reactant: C[Sn](C)(C)Cl
Solvent: COCCOC
Product: CC(C)c1cc([Sn](C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold suspension (0° C.) of Na (25% in toluene, 10 g, 104 mmol) in DME (100 mL) add a solution of trimethyltin chloride (9.4 g, 47.4 mmol) in DME (20 mL) dropwise. Stir the mixture at 0° C. for 3 h followed by addition of the solution of cold (0° C.) 4-chloro-2-isopropyl-pyridine (Comins & Mantlo (1985) J. Org. Chem. 50:4410-4411) (4.9 g, 31.6 mmol) in DME (20 mL). Stir the mixture at 0° C. for 2 h and warm to room temperature. Filter, concentrate the filtrate, and dilute the residue with ether. Filter and concentrate the filtrate. Distil the residue (bp 75-80° C. at 1 mm Hg) to afford the title compound as a light oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[NH:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]1.[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:13]1[CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:3]1[CH:4]=[C:5]([O:8][C:2](=[O:1])[CH3:3])[CH:6]=[CH:7][C:2]=1[O:1][C:5](=[O:8])[CH3:4])(=[O:19])[CH3:18]
Reactant: O=C(O)C1CSC(c2cc(O)ccc2O)N1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(OC(C)=O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
To a solution of 0.241 g (0.85 mmol) of 2-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (1:1 mixture of isomers at C2) was added 3 mL of pyridine, and the solution was cooled to −30° C. with a dry ice acetone bath. To the heterogeneous mixture was added 0.34 mL of acetyl chloride under constant stirring. The cooling bath was removed and the reaction mixture was allowed to warm up gradually to room temperature. After overnight stirring at room temperature, the solvent was removed under high vacuum. To the remaining oily residue were added 19 mL of water and 1 mL concentrated HCl. The precipitate was filtered and washed with 2×5 mL of water. After drying at high vacuum, 0.13 g of acetylated product (5) was obtained (34%), as a mixture of diastereoisomers and rotamers. 1H NMR (DMSO-d6) δ; 1.76 s, 1.79 s, 1.99 s, 2.03 s, 2.06 s, 2.26 s, 2.33 s, 2.34 s, 9H; 3.2-3.4m, 3H; 5.11 d, J=8 Hz and 5.36 d, J=8 Hz, 1H; 6.10 s, 6.20 s, 6.33 s and 6.36 s, 1H; 6.99-7.22 m, 2H; 12.95 bs, 1H.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[NH:19][C:20]([CH:22]=O)=[CH:21][C:13]2=3)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][C:34](=[O:40])[NH:35]3)[CH:28]=[CH:29][CH:30]=1>N1CCCCC1.C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[NH:19][C:20](/[CH:22]=[C:33]4\[C:34](=[O:40])[NH:35][C:36]5[C:32]\4=[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)[CH:39]=[CH:38][CH:37]=5)=[CH:21][C:13]2=3)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(C=O)cc32)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(/C=C4\C(=O)Nc5cccc(-c6cccc(F)c6)c54)cc32)CC1
Yield: 53.9 %

Procedure:
4-(1-Acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (56 mg) was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (40 mg) and piperidine (2 drops) in ethanol (1 mL) at rt for overnight. The solvent was concentrated and the residue was purified on a silica gel column to give 50 mg of the title compound as a yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:27]([O:29][CH3:30])=[O:28])[CH2:13]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCCCCC.CCOC(C)=O>[O:11]=[C:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:27]([O:29][CH3:30])=[O:28])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at −78° C. was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at −78° C. The formed slurry was stirred at −78° C. for 2 hr before addition of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced 1M HCl, 5% citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford (S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (14.8 g, 70% yield) as light brown viscous oil.
Reaction SMILES: COC([C@@H]1[C@H](O)CCN1C(OC(C)(C)C)=O)=O.C(OC(N1CC[C@H](O[Si](C(C)(C)C)(C)C)[C@H]1CO)=O)(C)(C)C.[OH:40][C@H:41]1[CH2:48][CH2:47][N:46]2[C@@H:42]1[CH2:43][N:44]([C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=1[CH3:60])[S:45]2(=[O:50])=[O:49]>>[Cl:59][C:53]1[C:52]([CH3:60])=[C:51]([N:44]2[CH2:43][C@H:42]3[N:46]([CH2:47][CH2:48][C@H:41]3[OH:40])[S:45]2(=[O:49])=[O:50])[CH:58]=[CH:57][C:54]=1[C:55]#[N:56]
Reactant: Cc1c(N2C[C@@H]3[C@@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Agent: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Product: Cc1c(N2C[C@@H]3[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from (2S,3R)-N-tert-Butyloxycarbonyl-3-hydroxy-2-pyrrolidinecarboxylic acid methyl ester by procedures analogous to those described in Example 7 (7A to 7F). HRMS (ES) m/z 328.0528 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[C:39]([O-])(O)=[O:40].[Na+]>C(O)=O>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH:39]=[O:40]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine (88 mg, 0.43 mmol) (Example 20) in 80% formic acid (3 mL) was heated to and maintained at reflux for 24 hours. The reaction was then cooled to room temperature, poured into saturated NaHCO3 (30 mL), and, after neutralization was complete, extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 15% EtOAc/hexanes afforded [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}formamide. Rf=0.20 (15% EtOAc/hexanes). LCMS=578.3 (M+1)+. 1H NMR (CD2Cl2, 600 MHz, rotamers present, ratio of major:minor ˜3:1. Data for major rotamer given.) δ 6.86-8.31 (m, 10H), 4.24-4.47 (m, 4H), 3.71 (s, 3H), 2.87 (m, 1H), 1.27 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 93.8 %

Procedure:
4-Chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89a, but using 2.8 g of 4-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 25.5 ml of a 5N aqueous potassium hydroxide solution. 1.81 g of 4-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[C:11]([O:12][CH:13]([F:15])[F:14])=[CH:10][N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:8]=1)#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[C:11]([O:12][CH:13]([F:15])[F:14])=[C:10]([N+:1]([O-:4])=[O:2])[N:9]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=2[Cl:27])[N:8]=1)#[N:6]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1OC(F)F
Agent: O=S(=O)(O)O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1OC(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming nitric acid (5 ml) was added to an ice-cooled solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethoxypyrazole (1.5g) in concentrated sulfuric acid (20 ml). The mixture was stirred at room temperature for 3 hours then poured into ice/water and extracted into dichloromethane (3×50 ml). The combined dichloromethane extracts were washed with water (30 ml), filtered through phase-separation paper and evaporated in vacuo. The resultant gum was purified by dry-column chromatography (eluant ether:hexane 1:3) t give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethoxy-5-nitropyrazole (0.3g) as a yellow solid, m.p. 72.5°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:32][CH2:33][N:34]([C:37](=[O:49])[CH2:38][N:39]3[C:43]([CH3:44])=[CH:42][C:41]([C:45]([F:48])([F:47])[F:46])=[N:40]3)[CH2:35][CH2:36]2)[CH:26]=1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(NC(=O)c3cccc(Cl)c3O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-2-hydroxy-benzoic acid (0.11 g, 0.65 mmol) in acetonitrile (10 mL) is added carbodiimidazole (0.11 g, 0.71 mmol). After stirring the reaction mixture at 60° C. for 2 h, 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (0.20 g, 055 mmol) is added, followed by 1,8-diazabicycloundec-7-ene (0.1 mL, 0.82 mmol). After stirring overnight at 60° C., the reaction mixture is cooled down to RT and then solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), 1N HCl (20 mL) and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. Cyclohexane is added dropwise to a solution of crude mixture in 1 mL ethylacetate to give after filtration 3-chloro-2-hydroxy-N-(3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-benzamide (Compound No. I.u.003) (0.148 g, 43%). 1H-NMR (400 MHz, MeOD): δ=1.61-1.76 (m, 1H), 1.77-1.90 (m, 1H), 1.92-2.03 (m, 2H), 2.33 (s, 3H), 2.81-2.99 (m, 2H), 3.31-3.41 (m, 1H), 4.09-4.16 (m, 1H), 4.61-4.70 (m, 1H), 5.62-5.81 (q, 2H), 6.45 (s, 1H), 6.95-7.01 (t, 1H), 7.11-7.18 (m, 1H), 7.33-7.39 (t, 1H), 7.51-7.60 (m, 2H), 7.63 (s, 1H), 7.91-7.92 (m, 1H). MS: m/z=521 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].O.NN>C(O)COCCOCCO>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH3:10])=[CH:3][C:2]=1[NH2:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1ccc(F)c(N)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a stirred mixture of 3'-amino-4'-fluoroacetophenone (7.56 g, 49.4 mmol) in triethylene glycol (60 mL) was added 4.94 g of sodium hydroxide. Neat hydrazine hydrate (7.2 mL) was added to the mixture in one portion via a syringe. This addition resulted in a slight exotherm (temperature around 50°). The reaction flask (three neck, equipped with claisen adapter and receiving flask) was then equipped with a heating mantle and the reaction heated to 100° C. for 1 hour, then 150° C. At the higher temperature distillate began to collect in the receiving flask. After 1 hour at 150° C. the reaction mixture was then heated to 180° C., while still collecting distillate. After 45 minutes at 180° C. thin layer chromatography indicated the complete absence of starting material and the appearance of a single major product. The reaction mixture was cooled to room temperature with an ice bath and poured into 100 mL of water. The aqueous mixture was extracted three times with ether (125 mL). The combined organic extracts were washed once with water, once with brine and then dried over potassium carbonate. Concentration of the organic extracts in vacuo afforded 2-fluoro-5-ethylaniline (6.82 g) as an amber liquid. This material was further purified by column chromatography (silica gel, hexanes/ethyl acetate: 2/1) to give 7.11 grams of product as a viscous liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(F)(F)F)cn1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(F)(F)F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 146 %

Procedure:
To a solution of crude 2-methyl-5-trifluoromethylpyridine from Step 1 (3.8 g) in CHCl3 (40 mL) was added m-chloroperbenzoic acid (3.0 g, 17.4 mmol) and the resulting mixture was stirred 5 hours at r.t. More peracid (1.5 g, 8.7 mmol) was added and the reaction stirred another 2 hours. Calcium hydroxide (3.0 g, 40.5 mmol) was added and the slurry was vigorously stirred 20 minutes before filtering through celite. Evaporation of the solvents gave 4.5 g of the title compound containing a little dioxane and CHCl3. This material was used without further purification.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(5-hydroxypentyl)-1-piperidinecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)=O.CC(C)=O.C[Li].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:9])[C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=O
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl{(1S)-1-[methoxy(methyl)carbamoyl]ethyl}carbamate (5.26 g) in tetrahydrofuran (300 mL) was cooled with dry ice/acetone under a nitrogen atmosphere, and 1.6 mol/L-methyllithium/diethyl ether solution (38.8 mL) was added. After stirring at the same temperature for 1.5 hr, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give the title compound as a colorless oil (yield: 4.48 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])=[O:8])([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])=[O:8]
Reactant: [H][H]
Reactant: Cc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)c2cccc(N)c2)c1C

Procedure:
To a solution of 1 (1 g) in 70 mL methanol and 30 mL of tetrahydrofuran was added 10% Pd/C (0.2 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo to obtain the product. NMR (300 MHz, CDCl3) δ 7.71 (1H, s), 7.55 (1H, d, J=9 Hz), 7.23 (1H, t, J=9 Hz), 7.19 (1H, s), 7.14 (1H, t, J=9 Hz), 7.04 (1H, d, J=9 Hz), 6.82 (1H, d, J=9 Hz), 3.84 (2H, b), 2.32 (3H, s), 2.20 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[OH:23])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(OCC)(=O)C>[OH:23][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:19]1
Reactant: O=COCc1ccccc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCNCC2O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reaction time: 0.17 h

Procedure:
The solution of 3.0 g of 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-ol in 30 ml of ethyl acetate is cooled to 0° C. with stirring and admixed with 30 ml of saturated aqueous sodium carbonate solution. At 0-5° C., 1.32 ml of benzyl formate are added dropwise. After 10 minutes, the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (2×250 ml). The organic phases are washed with brine (1×250 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (1:1 EtOAc-heptane); Rt=5.94. m.p. 71-73° C.