Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl.C(OCC)C.CN(C=O)C.C(Cl)CCl>[ClH:1].[CH:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH:30]4[O:31][CH2:32][CH2:33][NH:28][CH2:29]4)=[O:26])=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10]1)([CH3:4])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)O)cc3)CC2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)C4CNCCO4)cc3)CC2)CC1

Procedure:
To a stirred solution of 1-isopropyl4-[1-(4-carboxy-phenyl)-piperidin4-carbonyl]-piperazine hydrochloride (D9)(0.25 g), morpholine (0.035 ml), HOBT (0.03 g), TEA (0.16 ml) in DCM (10 ml) was added EDC (0.10 g). DMF (2 ml)was added and the reaction stirred under argon ovemight. The reaction mixture was then evaporated to a minimum and residue dissolved in DCM (50 ml) and washed with sodium hydrogen carbonate (3×50 ml) and then brine (50 ml). The organic layer was then dried (MgSO4) and evaporated to give the free base product. Free base was converted to the HCl salt by dissolving in DCM (5 ml) and treating with excess 1HCl in diethyl ether, evaporated and then crystallised from acetone to give the title compound (E30) as a white solid (0.03 g). MS electrospray (+ve) 429 (MH+). 1H NMR δ [DMSO-d6]: 10.85 (1H, s), 7.38 (2H, d, J=8.4 Hz), 7.08 (2H, m), 4.51 (1H, m), 4.22 (1H, m), 3.81 (2H, m), 3.68-3.35 (12H, m), 3.20-2.81 (6H, m), 1.74 (4H, m), 1.29 (6H, d, J=6.4 Hz).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH3:27][C@H:15]1[N:14]([CH2:13][CH:12]=[O:11])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (0.732 mL, 10.3 mmol) was added to a solution of oxalyl chloride (0.582 mL, 6.88 mmol) in DCM (13 mL) at −78° C. After stirring for 10 minutes, tert-butyl (3R)-4-(2-hydroxyethyl)-3-methylpiperazine-1-carboxylate (1.4 g, 5.7 mmol) in DCM (6.6 mL) was added over 15 minutes. The reaction was stirred at −78° C. for 1 hour, then triethylamine (3.99 mL, 28.6 mmol) was added. The reaction was stirred, with warming to room temperature, for 1 hour. The reaction mixture was diluted with DCM, washed twice with water and once with brine, dried over sodium sulfate and concentrated to afford product, used without further purification (1.20 g, 86%). 1H NMR (300 MHz, CDCl3): δ 9.72 (t, 1H), 3.90-3.65 (m, 2H), 3.43 (d, 1H), 3.15 (ddd, 1H), 3.04 (dd, 1H), 2.89-2.67 (m, 2H), 2.52-2.34 (m, 2H), 1.46 (s, 9H), 1.02 (d, 3H); LCMS (M+H2O+H)+: 261.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCc1nc(Cl)nc2c1SCC2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Yield: 55 %

Procedure:
9.7 g (42.3 mmol) of 2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VIII) and 25.7 mL (169.2 mmol) of 1-phenylpiperazine (III) are placed in 200 mL of dioxane (carried out in 10 batches), then reacted for 1 hour at 160° C. in the microwave. The reaction mixture is concentrated by evaporation, the residue is combined with 250 mL of water. Then the mixture is suction filtered, washed with water, and dried. The residue is stirred with acetonitrile, then recrystallized from isopropanol. 8.3 g of the product (I) (55%) is obtained as a powder (m.p. 121° C.). 1H NMR (400 MHz, DMSO): 7.22 (2H, t); 6.97 (2H, d); 6.79 (1H, t); 6.43 (2H, t); 3.81-3.69 (4H, m); 3.37-3.19 (4H, m); 3.19-3.09 (4H, m); 2.99 (2H, t); 1.62-1.47 (2H, m); 0.87 (3H, t).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][C:20]4[N:19]5[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:18]5=[CH:17][C:16]=4[CH:15]=3)=[CH:10][C:9]=2[C:36]([F:39])([F:38])[F:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][C:20]4[N:19]5[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:18]5=[CH:17][C:16]=4[CH:15]=3)=[CH:10][C:9]=2[C:36]([F:39])([F:37])[F:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)ccc12
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)ccc12
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl 2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.092 mmol) in DCM (1 mL) was added thioanisole (0.738 mmol) and TFA (1.85 mmol). The reaction mixture was stirred for 3 h. The solvent was removed under vacuum. The residue was purified by preparative HPLC/MS to give the title compound as a solid (26.1 mg). LCMS m/z=486.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.04 (m, 2H), 1.08-1.20 (m, 3H), 1.54-1.70 (m, 6H), 2.15-2.26 (m, 1H), 2.55 (dd, J=16.29, 8.08 Hz, 1H), 2.62 (d, J=6.44 Hz, 2H), 2.65-2.72 (m, 1H), 2.72-2:83 (m, 1H), 3.52-3.63 (m, 1H), 3.91-4.01 (m, 1H), 4.05-4.14 (m, 1H), 5.12 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.59 Hz, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.66 (d, J=7.71 Hz, 1H), 7.74 (s, 1H), 12.27 (bs, 1H).
Reaction SMILES: [Na].CO[C:4](=[O:37])[CH2:5][C:6]1=[N:7][N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:9](=[O:29])/[C:10]/1=[C:11](/[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[CH2:12][C:13]1[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=1.Cl.C[CH:40]([OH:42])C>>[CH2:22]([N:21]1[C:4](=[O:37])[CH:5]=[C:6]2[NH:7][N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:9](=[O:29])[C:10]2=[C:11]1[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:42][CH3:40])[CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(\Cc1ccc(OC)cc1)NCc1ccccc1
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Product: COc1cccc(Cc2c3c(=O)n(-c4ccccc4Cl)[nH]c3cc(=O)n2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.017 g, 0.75 mmol, 2 equiv.) in i-PrOH (2 ml), was treated with methyl[(4E)-4-[1-(benzylamino)-2-(4-methoxyphenyl)ethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (170 mg, 0.36 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 0.5 h, then cooled and neutralized to pH 6 by addition 1M HCl solution. i-PrOH were removed in vacuo and the crude was purified by flash chromatography to yield 24 mg of pure product 5-benzyl-2-(2-chlorophenyl)-4-(3-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione. Yield 14%. 1HNMR (500 MHz, DMSO-d6): 3.69 (s, 3H); 4.40-4.60 (m, 2H); 5.08-5.24 (m, 2H), 5.72 (s, 1H); 6.71-6.73 (m, 2H), 6.80-6.82 (m, 1H); 7.02-7.03 (m, 2H); 7.21-7.25 (m, 3H); 7.28-7.31 (m, 3H); 7.47-7.49 (m, 2H); 7.62-7.66 (m, 2H). MS (ESI+): 472.9; MS (ESI−): 470.7.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:21])[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.CO>O.C(O)(=O)C>[Br:21][C:11]1[N:10]([CH:9]2[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 2.5 h
Yield: 61.9 %

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (600 mg, 1.15 mmol) was added to a stirred mixture of sodium carbonate (122 mg) in water (2 mL)-ethanol (10 mL)-methanol (10 mL). After 2.5 hours at ambient temperature, the pH was adjusted to 7 with glacial acetic acid. Volatiles were removed in vacuo and the residue triturated with water (5 mL) and filtered to give white solid. Recrystallization of the solid from 1:1 ethanol-methanol gave title compound as a white powder (282 mg, 62%), m.p. 208°-211° C.; 1H-NMR (DMSO-d6)δ: 8.23, (s, 1, benzimidazole H7), 7.95 (s, benzimidazole H4), 5.13 (t, J=4.1 Hz, 1, CH2OH), 5.03 (d, J=6.2 Hz, 1, OH), 5.0-4.85 (m, 1, H5), 4.71 (d, J=3.5 Hz, 1, OH), 4.55-4.45 (m, 1, H1), 3.85-3.80 (m, 1, H2), 3.7-3.6 and 3.55-3.45 (both m, 1 each, OCH2), 2.2-1.95 (m, 3, H3 and 2H4); mass spectrum (CI): 395 (M+1).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][C:49]=1[F:57].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[C:49]([F:57])[CH:50]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (74 mg, 0.05 eq.) and 4-chloro-3-fluoro-phenylboronic acid (825 mg, 2.5 eq.). 30 mL of MeOH and 3 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (480 mg, described herein above). The reaction mixture was heated at 55° C. for 3 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 261 mg (33%) of the title product as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.ClCCl>C(#N)C>[CH2:1]([N:8]1[C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[N:25][N:24]=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1Cc1nnnn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolution of the white solid isolated in Step A (8.02 g, 27.2 mmol) in acetonitrile (100 mL) was achieved by heating to reflux. After the solution was cooled to 0° C., NaN3 (2.30 g, 35.4 mmol) and trifluoromethanesulfonic anhydride (10 g, 35.4 mmol) were added. The resulting solution was then stirred at room temperature overnight. Dichloromethane (200 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution three times and brine one time and then dried over MgSO4. The solution was filtered and concentrated to yield 2-(1-benzyl-1H-tetrazol-5-ylmethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:30])[NH:25][CH2:26][CH:27](C)C)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:30])[NH:25][CH2:26][CH3:27])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:31][CH:32]=1
Reactant: CC(C)CNC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A suspension of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(isobutylcarbamoyl)methyl]indoline (0.07 g) obtained in Example 152 and active manganese dioxide (0.07 g) in chloroform (30 ml) was vigorously stirred at 50° C. overnight. Then the reaction mixtures were filtered through celite and the residue was washed with chloroform. After concentrating the filtrate under reduced pressure, the residue was recrystallized from chloroform/hexane to give the title compound (0.05 g) as a white powder (yield: 70.0%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 94 %

Procedure:
4-Bromo-benzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.66 g, 20.3 mmol, 94%) was obtained as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br:16]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl.CO.C(Cl)Cl>[Br:16][C:12]1[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][S:2](=[O:15])(=[O:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 174 mg, 0.77 mmol) in 20 mL of 3:1 DCM/MeOH at 0° C. was added N-bromosuccinimide (NBS) (137 mg, 0.77 mmol) in 5 mL of DCM under Ar. The mixture was warmed to RT and stirred for 1 h under Ar. Treated with 100 mL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-3% EtOAc/DCM) gave 155 mg (66%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 7.28 (d, 1H, J=2.0 Hz), 6.97 (dd, 1H, J=8.3, 2.0 Hz), 6.73 (d, 1H, J=8.3 Hz), 4.07 (br s, 2H), 3.09-3.14 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.26-2.39 (m, 2H), 2.12-2.21 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C11H14BrNO2S, 304.0 (M+H), found 304.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[OH:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1.Cl[CH2:18][C:19]#[N:20].O>CS(C)=O>[OH:16][CH2:15][C:10]1[C:9]([O:8][CH2:18][C:19]#[N:20])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCc1ncccc1O
Reactant: N#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1cccnc1CO
Temperature: 0 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
Potassium carbonate (8.57 g, 0.062 mol) was stirred in DMSO (30 ml) under nitrogen at room temperature for 20 min. The mixture was cooled to 0° C. and 3-hydroxy-2-(hydroxymethyl)pyridine hydrochloride (5.0 g, 0.031 mol) was added. The slurry was stirred at 0° C. for 1.5 h before the addition of chloroacetonitrile (1.96 ml, 2.34 g, 0.031 mol). The mixture was allowed to warm to room temperature and stirred under nitrogen for 72 h. Water (100 ml) was added, and the resultant solution was extracted with dichloromethane (3×100 ml), the organic layers were combined, washed with water (1×100 ml) and saturated sodium chloride solution (1×100 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a dark brown solid (3.04 g). 1H NMR (250 MHz, CDCl3) δ 4.77 (2H, s), 4.85 (2H, s), 7.26-7.30 (2H, m), 8.32 (1H, m); MS (ES+) m/e, 165 [MH]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30]Br)[CH2:24]1)=[O:22])[CH3:19].O>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: Oc1ccccc1Cc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
Sodium hydride (0.8 g, 20 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 2-benzylphenol (1.8 g, 10 mmol) in toluene (30 ml) placed under an atmosphere of nitrogen. The mixture was stirred for 30 minutes and (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.5 g, 10 mmol, EP 374801) was added portionwise. The reaction mixture was stirred for 2 h at ambient temperature and water (50 ml) was added. The phases were separated and the organic phase was extracted with a 10% citric acid solution (200 ml). This acidic solution was extracted with a small portion of toluene and the organic extracts were discarded. To the acidic aqueous phase 4N sodium hydroxide was added until pH 7-8 and the mixture was extracted with ethyl acetate (150 ml). The organic extract was dried (Na2SO4) and the solvent was evaporated in vacuo to give 1.7 g of (R)-1-(2-(2-benzylphenoxy)ethyl)-3-piperidine-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:12][O:13][N:14]=[C:15]([CH:17]([NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[CH3:18])[CH3:16]>C1C=CC=CC=1>[CH3:12][O:13][N:14]=[C:15]([CH:17]([N:19]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:18])[CH3:16]
Reactant: CON=C(C)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Yield: 782.7 %

Procedure:
A sample of 54.2 g (0.048 mol) chloroacetyl chloride and a sample of 34.8 g (0.44 mol) pyridine was added over a 25-minute period to a solution of 97.0 g (0.44 mol) 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime maintained at 45° C. in 500 ml benzene. The pyridine was added slightly faster than the chloroacetyl chloride. The reaction temperature rose to about 50°-58° C. during the addition. The reaction mixture was then cooled, washed with water, washed with 5% aqueous sodium bicarbonate solution, stirred with silica gel, filtered and evaporated under reduced pressure to give 111.5 g of 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The infrared spectrum of the product showed carbonyl absorption at 5.9 micron and O--CH3 absorption at 9.5 micron. The product is tabulated in Table I as Compound No. 5-B.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:63]=[CH:62][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 80 mg (0.3 mmol) of (4-tert-butyl-benzyl)-phenethyl-amine in 1 ml DMF were added. After stirring for 5 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 100 mg white solid (80%). MS (ISP) 411.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(O)C.C(#N)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 71.9 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20 mmol), K2CO3 (2.8 g) and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was allowed to cool, filtered, and the filtrate was concentrated to 9.9 g of a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2:3 g of an off-white solid. The solid was dissolved in ethanol and fumaric acid (0.62 g, 1.1 eq.) was added. Upon concentration of the ethanol, a crude, brown solid was collected, which was taken up in refluxing acetone. Upon cooling, a white solid crystallized from solution yielding 2.2 g (19%) of 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone fumarate as a white solid, m.p.=139°-141° C.