Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][C:28]=2[O:36][C:37]([F:40])([F:38])[F:39])(=[O:34])=[O:33])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 g, 0.0047 mol) in CH2Cl2 were added diisopropylethylamine (1.63 mL, 0.0093 mol) and 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (1.03 mL, 0.0051 mol). The reaction mixture was stirred at ambient temperature for 1 hr and then washed with water. The aqueous layer was extracted with CH2Cl2 (twice), the organic layers were combined, dried over MgSO4, and concentrated. The resulting precipitate was recrystallized with CH2Cl2 and hexanes to give trans-[4-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-cyclohexyl]-carbamic acid tert-butyl ester (2.39 g, 0.0046 mol, 99%).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][C:12]1([CH3:20])[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[CH:14]=[CH:13]1.[Cl-].[NH4+]>C(OCC)C>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]2([OH:19])[CH:16]([CH3:18])[CH2:17][C:12]([CH3:20])([CH3:11])[CH:13]=[CH:14]2)=[CH:5][CH:4]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1CC(C)(C)C=CC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CC(C)(C)C=CC1(O)Cc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a slurry of magnesium turnings (66 g, 2.73 g.atoms) in diethyl ether (300 ml) was added a solution of 4-chlorobenzyl chloride (418 g, 2.6 moles) in diethyl ether (1500 ml) at such a rate as to maintain gentle reflux. After a further 30 minutes, a solution of 4,4,6-trimethylcyclohex-2-en-1-one (340 g, 2.46 moles) in diethyl ether (350 ml) was added, again maintaining a gentle reflux. After 1 hour the mixture was added into saturated aqueous ammonium chloride (4 liters) and the phases separated. The ether phase was back-washed with water (1 liter) and used directly in the next reaction. A small portion of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-2-en-1-ol was isolated for characterisation (gas chromatography analysis showed two isomers in approximately equal amounts).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1ccccc1CBr
Product: O=Cc1cn(Cc2ccccc2F)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 2-fluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 1.46 g of 1-(2-fluorobenzyl)indole-3-carbaldehyde as yellowish brown crystals. The yield thereof was found to be 96%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[C:18](/[C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)\[C:19]#[N:20])=[CH:3][CH:2]=1
Reactant: N#CCc1cccs1
Reactant: O=Cc1ccnc2ccccc12
Product: N#C/C(=C\c1ccnc2ccccc12)c1cccs1
Yield: 66.8 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 2-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 175 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Reactant: CNc1ccccc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-fluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2/hexanes:ethylacetate) provided 169bp. 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 1 H), 7.31 (m, 1 H), 7.18-7.22 (m, 2 H), 6.80 (s, 1 H), 6.94 (d, J=8.3 Hz, 1 H), 6.77 (d, J=8.2 Hz, 1 H), 6.60 (s, 1 H), 5.00 (s, 2 H), 3.42 (s, 3 H), 2.26 (s, 3 H). LCMS (ESI) m/z: 354.1
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:5]=2[O:4]1.[F:22][C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].CN(C)C=O>[Cu]I.C1(C)C=CC=CC=1>[F:28][C:24]([F:29])([C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:20][F:21])([CH2:2][F:1])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:6]=2[CH:15]=1)[C:23]([F:31])([F:30])[F:22]
Reactant: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FCC1(CF)C=C(c2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Temperature: 160 °C
Yield: 79 %

Procedure:
A mixture of 1.11 g of 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran, 1.17 g of potassium pentafluoropropionate, 1.18 g of copper (I) iodide, 20 ml of N,N-dimethylformamide and 7 ml of toluene was stirred at 160° C. under nitrogen gas atmosphere with heating for 3 hours while toluene was distilled off. Ether and water were added thereto and the mixture was filtered using Celite. The mother liquor was extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.86 g of oily 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
A suspension of 18 (2.91 g, 8.68 mmol), Cs2CO3 (4.25 g, 13.02 mmol) and DMF (anhydrous, 40 mL) was stirred at room temperature for 1.5 h. To the mixture was then added methyl iodide (0.83 mL, 13.02 mmol), and stifling was continued for an additional 3 h at the ambient temperature. The mixture was then partitioned between water (150 mL) and dichloromethane (150 mL), aqueous layer was separated and washed with dichloromethane (3×300 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired methyl ester 19 (3.41 g, quant yield): 1H NMR (500 MHz, CDCl3) δ 1.26 (m, 12H), 1.47 (m, 2H), 1.52 (m, 2H), 2.28 (m, 2H), 3.16 (m, 2H), 3.66 (s, 3H), 5.10 (s, 2H), 7.32 (m, 5H); m/z (ESI) 350 [M+H]+.
Reaction SMILES: CN[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[NH:20])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.C1C2[N:29]([CH2:30]C=C(C3C4C(=CC=C(N)C=4)NC=3)C2)[CH2:28]C1.I.CSC(C1SC=CC=1)=N>C(O)C>[CH2:3]1[CH:4]2[N:29]([CH2:30][CH:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[NH:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:5]2)[CH2:28][CH2:8]1
Reactant: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1)c1cccs1
Reaction time: 24 h
Yield: 79 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2×20 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15); ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: CN(C)C=O.[CH:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]3[NH:17][C:16]([C:18]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[C:19]4[CH:47]=[CH:46][C:21](=[C:22]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:23]5[CH:39]=[CH:38][C:25](=[C:26]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)[C:27]6[CH:28]=[CH:29][C:30]=2[N:31]=6)[N:24]=5)[NH:20]4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=1.[Pd:54](Cl)Cl>O>[C:48]1([C:18]2[C:16]3[NH:17][C:13](=[CH:14][CH:15]=3)[C:12]([C:9]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)=[C:30]3[N:31]=[C:27]([CH:28]=[CH:29]3)[C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:25]3[NH:24][C:23]([CH:39]=[CH:38]3)=[C:22]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:21]3=[N:20][C:19]=2[CH:47]=[CH:46]3)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Pd:54]
Reactant: Cl[Pd]Cl
Reactant: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Solvent: CN(C)C=O
Solvent: O
Product: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Product: [Pd]

Procedure:
Palladium tetraphenylporphyrin is prepared according to the experimental method described by A. D. Adler, F. R. Longo, F. Kampas and J. Kim, J. Inorg. Nucl. Chem. Vol. 32, p. 2443 (1970). To 300 ml of boiling dimethylformamide are added 3 g of tetraphenylporphyrin. After dissolution is effected, 0.9 g of palladium chloride is added. The mixture is refluxed for 10 minutes, then cooled in an ice bath and poured into 300 ml of water. The precipitate is filtered, washed with water and dried.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].Cl.[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)=[CH:7][CH:8]=1)#[N:13]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: N#Cc1ccc(NC(=O)CCl)cc1
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-cyano-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 113-116° C. (diethylether)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]#[N:16])[C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[NH:26][N:25]=[N:24][N:16]=2)[C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC[C@@H]1CC[C@@H](OCc2ccccc2)[C@@H]1c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc([C@@H]2[C@H](Cc3nnn[nH]3)CC[C@H]2OCc2ccccc2)cc1
Temperature: 125 °C
Yield: 64.2 %

Procedure:
To a solution of 342 mg of product from Step D in 7 mL of DMF was added 215 mg of sodium azide and 176 mg of ammonium chloride. The reaction was heated at 125° C. for 4 days and then cooled and diluted with water and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography with 5% methanol in methylene chloride to obtain 250 mg of title compound as a oil. T.l.c. (5% methanol in methylene chloride) Rf =0.2. Mass spec (NH3 /CI): 353(M+1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([Cl:14])[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[NH:17]C(=O)C>O.CCO>[Cl:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([Cl:14])[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COc1cc(NC(C)=O)c(Cl)c(C(F)(F)F)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)c(C(F)(F)F)c1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A 2 M solution of KOH in water (1.87 mL) is added to a solution of N-(2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl)-acetamide (104 mg, 0.344 mmol) in EtOH (3 mL). After stirring for 3.5 h at 80° C. followed by cooling to RT, the solvent is evaporated and the residue is taken up in EtOAc and a saturated aqueous solution of NaHCO3. The separated aqueous layer is extracted twice with EtOAc. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated, providing the title compound: ESI-MS: 258/260 [M-H]−1; tR=4.8 min (system 1); TLC: Rf=0.54 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][Cl:18]>O1CCCC1>[ClH:1].[ClH:18].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][Cl:18])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: ClCCBr
Solvent: C1CCOC1
Product: Cl
Product: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 112 %

Procedure:
A mixture of 15.0 g of 1-(4-chlorobenzyl)piperazine, 14.4 g of 1-bromo-2-chloroethane and 150 ml of tetrahydrofuran was refluxed for 8 hours. The solvent was removed in vacuo, and 2N sodium hydroxide was added to the residue. The product was extracted with methylene chloride, and the extract was dried (sodium sulfate) and concentrated. The salt was precipitated with ethereal hydrochloric acid to give 13.8 g (56% of theory) of 1-(4-chlorobenzyl)-4-(2-chloroethyl)piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][CH3:13])[CH2:3][CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(OO)(=[O:16])C.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:12]([C:2]1([CH2:1][OH:16])[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][O:7][CH2:6]2)[O:11]1)[CH3:13]
Reactant: CC(=O)OO
Reactant: C=C(CC)CCC1(O)CCCOC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1(CO)CCC2(CCCOC2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of 5.75 g of tetrahydro-3-(3-methylenepentyl)-2H-pyran-3-ol in 40 ml methylene chloride was added in four portions, 6.5 g of 40% peracetic acid in acetic acid containing 145 mg of anhydrous sodium acetate. A temperature increase from 20° C. to 37° C. resulted. The resulting solution was refluxed for 1 hour and stirred at ambient temperature for 4 hours. The resulting mixture was diluted with 60 ml of methylene chloride and washed with 100 ml of water. The organic phase was washed successively with two 100 ml portions of 25% potassium carbonate, and 100 ml of saturated sodium chloride, dried with MgSO4 and vacuum concentrated to leave 5.7 g of the desired product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].Cl>CN(C)C=O.O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(CCCCCc2ccc(O)cc2)O1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
To a solution of 5-[5-(4-hydroxyphenyl)pentyl]-2,4-oxazolidinedione (0.9 g) in N,N-dimethylformamide (DMF) (40 ml) was added sodium hydride (60% in oil, 0.28 g). The mixture was stirred for 15 minutes at room temperature, to which was then added 4-chloromethyl-5-methyl-2-phenyloxazole (0.85 g), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water, acidified with 2N HCl, and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-chloroform (1:5, v/v) was obtained 5-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-2,4-oxazolidinedione (0.86 g, 58%). Recrystallization from dichloromethane-isopropyl ether gave colorless prisms, m.p.120-121° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:21])(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([N:32](C(C)C)CC)(C)C.[NH:38]1[C:46]2[C:41](=[CH:42][C:43]([C:47]([OH:49])=O)=[CH:44][CH:45]=2)[CH:40]=C1.CCN=C=NCCCN(C)C>ClCCl.O>[CH3:21][C@H:9]1[CH2:10][C@@H:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][N:8]1[C:1]1[NH:38][C:46]2[C:41]([CH:40]=1)=[CH:42][C:43]([C:47]([NH2:32])=[O:49])=[CH:44][CH:45]=2
Reactant: CC1CC(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](Cc2ccccc2)CCN1c1cc2cc(C(N)=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.8 %

Procedure:
To a solution of 1-BOC-2-methyl-4-benzylpiperidine (0.29 g, 1.0 mMol) in 5 mL of dichloromethane was added trifluoroacetic acid (TFA) (0.5 mL). After stirring at rt for 10 h the reaction mixture was evaporated in vacuo and azeotroped twice with dichloromethane and twice with hexane. The residue was dissolved in 5 mL of dichloromethane and diisopropylethylamine (1.6 mL, 10 mMol) was added. In a separate flask a mixture of 5-indolecarboxylic acid (0.19 g, 1.2 mMol) and EDAC (0.23 g, 1.2 mMol) was dissolved in 15 mL of dichloromethane and stirred at rt for 5 min. To this reaction mixture was added the first solution, and the resulting mixture stirred at rt for 20 h. The reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water and brine. The extract was dried over Na2SO4 and evaporated. The residue was chromatographed on a column of silica gel with 1% MeOH-dichloromethane. Evaporation of the desired fractions gave 0.18 g (54%) of the product as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH:20]=[N:19][C:18]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]1=2.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:18]2[N:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH:12]=[O:11])[C:17]=2[N:26]=1
Reactant: COc1ccc2ncc(=O)n(CCCCO)c2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CCCC=O)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A solution of oxalyl chloride (0.155 ml, 1.81 mmol) in dichloromethane (1.5 ml) was cooled to −78° C., a solution of dimethyl sulfoxide (0.128 ml, 1.81 mmol) in dichloromethane (1.5 ml) was added dropwise under a stream of argon and the solution was stirred at the same temperature for 15 minutes. A solution of 4-(4-hydroxybutyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (150 mg, 0.60 mmol) in dichloromethane (1.5 ml) was added dropwise to the reaction solution and the mixture was further stirred at the same temperature for 1.5 hours. Triethylamine (0.503 ml, 3.61 mmol) was added to the reaction solution, the temperature was raised to room temperature and a saturated ammonium chloride solution and dichloromethane were added. The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure to yield 148 mg (100%) of the title compound in the form of a yellow solid. The product was used as such for the next step without purification.