Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C=O)ccc1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of methyl 5-formyl-2-hydroxybenzoate (21.76 g), triethylamine (13.46 g), ethyl acetate (300 mL) was added dropwise methanesulfonyl chloride (15.24 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-formyl-2-methanesulfonyloxybenzoate as a colorless oil (31.20 g, yield 100%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:9][CH:8]=1.C(=O)=O.C(O)(C)C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)N2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Boron tribromide (10 ml in 25 ml of methylene dichloride) was added dropwise over a 30 minute period to a solution of 15.5 g of 1-[2-(4-methoxyphenylamino)benzoyl]piperidine in 80 ml of dry methylene dichloride cooled in a bath of Dry Ice and isopropyl alcohol. The reaction mixture was allowed to warm to room temperature and to stand overnight. The solvent was then removed in vacuo, and the residue was treated with 100 ml of distilled water and made basic with about 250 ml of saturated sodium bicarbonate solution. The solid which formed was collected by filtration and recrystallized from ethanol to give 10.2 g of 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, colorless powder, m.p. 199°-201° C. (decompn.).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH:19]([NH:22][N:23]=[C:24]([NH2:26])[CH3:25])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:26]=[C:24]([NH:23][NH:22][CH:19]([CH3:21])[CH3:20])[CH3:25])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(N)=NNC(C)C
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NNC(C)C

Procedure:
Coupling of 28 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 9-bromo-N-(1-(2-isopropylhydrazinyl)ethylidene)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 34, which forms III upon heating.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[N+:21]([O-])=O)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:16]=1[N+:24]([O-])=O)[CH:11]=2)[CH3:2].[H][H]>[Pd].C(OC(=O)C)(=O)C>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[NH:21][C:5](=[O:6])[CH3:4])=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:16]=1[NH:24][C:15](=[O:27])[CH3:14])[CH:11]=2)[CH3:2]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c([N+](=O)[O-])c3nc2c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(NC(C)=O)c3nc2c1NC(C)=O

Procedure:
3,6-bis(2-diethylaminoethoxy)-4,5-dinitroacridine is reduced with hydrogen and palladium catalyst in acetic anhydride as the solvent in the reduction, giving the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(S(C)(=O)=O)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methanesulfonyl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (CDCl3): δ 1.45-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44-3.02 (m, 7H), 3.91 (s, 3H), 3.94 (s, 3H), 6.88-7.85 (m, 7H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(=O)OCC>>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-phenylpiperazine (193 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4].C([O-])(O)=O.[Na+]>CS(C)=O.CC(C)=O>[F:21][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[N:10]=[C:9]2[N:16]([CH3:19])[CH2:17][CH2:18][C:8]=12)(=[O:5])=[O:4]
Reactant: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1CO)CCN2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)CCN2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 134 mg of alcohol 30 in 2 mL of DMSO and 2 mL of acetone was added 116 mg of IBX. The reaction mixture was stirred at room temperature for 16 h then cooled to 0° C., 5 mL of a mixture of 5% NaHCO3 and 5% of NaS2O3 was added by syringe slowly. After stirred for additional 20 min the mixture was extracted with three portions of 5 mL of ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4. After the solvent was removed under diminished pressure, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:10 EtOAc-hexanes gave product 31 as white crystal: yield 121 mg, (91%). Silica gel TLC Rf 0.20 (1:4 EtOAc-hexanes); 1H NMR (CDCl3, ppm): δ 2.70 (s, 3H), 3.09 (s, 3H), 3.18 (t, J=8.5 Hz, 2H), 3.72 (t, J=8.5 Hz, 2H), 10.09 (s, 1H). 13C NMR (CDCl3, ppm): 623.21, 24.06, 31.48, 51.19, 112.28, 112.40, 120.01, 151.18, 165.51, 166.54, 185.22; 19F NMR (CDCl3, ppm): δ−73.54 (s, 3F); HRMS (APCI+) calculated for C11H12N2O4SF3 (M+H+) 325.0470. found 325.0465.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][N:10]=1)[CH3:3].[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:11][N:10]=2)[CH:19]=[CH:20][C:21]=1[NH2:22])[CH3:1]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A mixture of 2-[3-(1-methylethoxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (39.89 g), iron powder (31 g), calcium chloride (1.3 g), ethanol (400 mL) and water (100 mL) was stirred at 80° C. for 3 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water and brine were added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether-hexane to give the title compound (32 g, 88%) as a brownish solid. MS 323 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:19])[CH2:15][CH2:16][C:17]#[CH:18]>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:19]
Reactant: C#CCCCO
Reactant: COc1ccc2nccc(Br)c2n1
Product: COc1ccc2nccc(CCCCC=O)c2n1
Yield: 50 %

Procedure:
This intermediate was prepared starting from 8-bromo-2-methoxy-[1,5]naphthyridine (2 g, 8.3 mmol) and 4-pentyn-1-ol (1 mL, 1.3 eq.) and following the procedures of Example 29 step 29.i and Example 33, steps 33.i and 33.ii. The title aldehyde was isolated as a yellow oil (1.1 g, 50% yield over 3 steps).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:11]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:11][C:5]1[C:6]([OH:10])=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][NH:1]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2[nH]ncc2c1
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2[nH]ncc2c1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of the 1H-indazol-5-ol (1.60 g, 0.0119 mol) obtained in Reference Example 4 in tetrahydrofuran (50 ml) was added N-chlorosuccinimide (1.59 g, 0.0119 mol) at room temperature. After 1 hour, the mixture thus obtained was heated to 40° C., and after another 2 hour, the mixture was heated to 50° C. After 5 hours, the reaction solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-chloro-1H-indazol-5-ol (1.7365 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH:11]([CH3:13])[CH3:12]>>[CH:11]([C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9])([CH3:12])[CH3:10]
Reactant: CC(C)C(=O)O
Reactant: Cc1ccnc(N)c1N
Product: Cc1ccnc2nc(C(C)C)[nH]c12

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and isobutyric acid (0.19 ml, 2 mmol) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (20:1) to give the pure product (0.25 g, 72%) as a tan colored solid. 1H NMR (300 MHz, CDCl3): 8.21 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz), 3.40 (m, 1H), 2.71 (s, 3H), 1.55 (d, 6H, J=7 Hz). FAB-MS: m/e 176 (M+H).
Reaction SMILES: [Cl:1][Ta:2]([Cl:6])(Cl)(Cl)Cl.[CH:7]([OH:10])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[Cl:1][Ta:2]([Cl:6])([O:10][CH:7]([CH3:9])[CH3:8])([O:10][CH:7]([CH3:9])[CH3:8])[O:10][CH:7]([CH3:9])[CH3:8]
Reactant: Cl[Ta](Cl)(Cl)(Cl)Cl
Reactant: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)O[Ta](Cl)(Cl)(OC(C)C)OC(C)C
Temperature: 45 °C

Procedure:
20.7 g of pentachlorotantalum was dispersed in 100 ml of toluene, to which 88.5 ml of isopropyl alcohol was added dropwise in a nitrogen gas atmosphere. The resultant solution was stirred at room temperature for 1.5 hours, and was then heated to 45° C. to remove the solvent therefrom by distillation. As a result, 24.8 g of dichlorotriisopropoxytantalum [TaCl2 (OCH(CH3)2)3 ] was obtained as a residue in the form of white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].CCN(C(C)C)C(C)C.Cl[CH2:52][CH:53]1[CH2:55][O:54]1>CN(C=O)C>[Cl:40][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([N:1]3[CH2:55][CH:53]([OH:54])[CH2:52]3)[C@H:3]([OH:41])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]2[N:18]=1
Reactant: ClCC1CO1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N4CC(O)C4)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg, 0.046 mmol) was dissolved in DMF (1 ml) in a 4 ml vial. DIPEA (0.25 ml, 1.431 mmol) was added and the mixture warmed to 70° C. A solution of 2-(chloromethyl)oxirane (100 μl, 1.279 mmol) in DMF (1 ml) was added slowly. The reaction mixture was kept at 70° C. for 30 minutes. The crude reaction mixture was filtered through a MCX cartridge (Waters, 5 g adsorbent). The cartridge was washed with MeOH and the product eluted with a 1:1 mixture of (CH3CN+2 molar solution of NH3 in MeOH). Evaporation to dryness gave 30 mg of (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile. The crude was used “as is” in the following deprotection
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[F:25]>CN(C=O)C.C1COCC1>[F:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(F)cccc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
To a suspension of NaH (5.2 g, 130 mmol) in DMF/THF (110 ml/45 ml) was added diethyl malonate (19 ml, 125 mmol) dropwise and the mixture was stirred for 30 min at room temperature. To the mixture was added 2-(Bromomethyl)-1-fluoro-3-nitrobenzene (29 g, 124 mmol) in DMF/THF (40 ml/30 ml) and the resulting mixture was refluxed for 3 h. After cooling, the excess reagent was quenched with brine and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to afford diethyl 2-(2-Fluoro-6-nitrobenzyl)malonate (48 g) as a brown oil. This crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CS(O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]1)(=O)=O.O>CN(C)C=O>[CH3:15][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][N+:11]=1[O-:14]
Reactant: C[C@H]1CCCN(CCCOS(C)(=O)=O)C1
Reactant: Cc1cc(-c2ccc(O)cc2)cc[n+]1[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(OCCCN3CCC[C@H](C)C3)cc2)cc[n+]1[O-]
Temperature: 25 °C

Procedure:
A A mixture of 4-(4-hydroxyphenyl)-2-methylpyridine 1-oxide (55 mg), potassium carbonate (187 mg) and (3S)-1-(3-methanesulfonyloxypropyl)-3-methylpiperidine hydrochloride in N,N-dimethylformamide (3 mL) is heated at a temperature close to 65° C. overnight and cooled back to room temperature. Water (5 mL) is added; the solution is washed with methylcyclohexane (twice 10 mL) and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (eluent dichloromethane/methanol from 95/5 to 80/20). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is diluted in ethanol, oxalic acid (7 mg) is added and solvent is removed under reduced pressure to give 32 mg of (3S)-2-methyl-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, oxalate as a brown crystalline material.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O-:3])=[O:2].C([O-])(C)(C)C.[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:39]([O:38][C:36]([CH2:35][N:17]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:37])[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
60 g (155 mmol) of N-(2,4-dinitro-1-naphthyl)-4-methylphenylsulfonamide (J. Soc. Chem. 1935, 1855) were dissolved in 500 ml of anhydrous dimethylformamide under protective gas and 19.1 g (170 mmol) of potassium tert-butanolate were added a little at a time. The mixture was stirred at room temperature for about 30 minutes, and then 25.9 g (155 mmol) of ethyl bromoacetate dissolved in 50 ml of anhydrous dimethylformamide were added dropwise. The mixture was then heated at 100° C. for 90 minutes and, after cooling, poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was heated with a mixture of 50 ml of toluene and 100 ml of ethanol and the resulting crystals were filtered off with suction to yield 55.7 g (76%) of the product. Melting point 106°-107° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)[OH:32]
Reactant: COc1ccccc1OC
Reactant: O=CC1CCN(CCc2ccc(F)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL) under argon at 0° C. was added n-BuLi (2.7 mL of a 2.5 M solution in hexane, 6.75 mmol). After stirring 2.5 h, the solution was cooled to −78° C. and treated with 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g/ 5.5 mmol) in THF (25 mL) via an addition funnel. The cooling bath was removed and the solution was allowed to stir for 2 hours. Water was added, the layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from hexane to afford racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as shiny white needles, m.p. 126-127° C. Anal. Calcd for C22H28FNO3: C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1Cl
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccccc2Cl)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 2-chlorobenzaldehyde gave the title compound as white crystals m.p.: 154° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]([CH:19]([CH2:25][N+:26]([O-])=O)[CH2:20][C:21]([O:23]C)=O)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:17][C:15]1[C:14]([CH3:18])=[C:13]([CH:19]2[CH2:20][C:21](=[O:23])[NH:26][CH2:25]2)[C:12]([O:29][CH3:30])=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:10])[CH:16]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of methyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-4-nitrobutanoate (0.92 g, 2.1 mmol) in methanol (15 mL) was treated with nickel chloride hexahydrate (0.99 g, 4.1 mmol) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and treated with sodium tetrahydroborate (0.84 g, 22 mmol) in four portions. The ice bath was removed and the reaction mixture was stirred for 30 min and heated at 60° C. for 4.5 hours. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and EtOAc (50 mL) and filtered over Celite. The Celite was washed with EtOAc and the filtrate was concentrated to give the desired product as a mixture of diastereoisomers at the lactam carbon. The mixture of diastereoisomers was separated by chiral HPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 9 mL/min, column loading ˜3 mg/injection) to give peak 1 (0.39 g, 49%, retention time: 6.25 min) and peak 2 (0.32 g, 40%, retention time: 9.34 min) as white solids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]3[C@H:12]([CH2:13][O:14][CH:15](O)[C:16]3=[O:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br-:20].[C:21]1([PH+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br-:20].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]3[C@H:12]([CH2:13][O:14][CH:15]([P+:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:16]3=[O:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C(O)OC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: O=C1C([P+](c2ccccc2)(c2ccccc2)c2ccccc2)OC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of (6R*,9aS*)-6-(4-fluorophenyl)-3-hydroxyhexahydropyrido[2,1-c][1,4]oxazin-4-one (26 mg) and triphenylphosphonium bromide (40 mg) in acetonitrile (3 mL) was heated under reflux for one hour and 30 minutes. The reaction solution was left to cool to room temperature, and then the solvent was evaporated under reduced pressure to obtain 57 mg of the title compound. The property value of the compound is as follows.